Physiol Rev 89: 991–1023, 2009;
doi:10.1152/physrev.00044.2008.
Transglutaminases and Disease: Lessons From Genetically
Engineered Mouse Models and Inherited Disorders
SIIRI E. IISMAA, BRYONY M. MEARNS, LASZLO LORAND, AND ROBERT M. GRAHAM
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute and University
of New South Wales, Sydney, New South Wales, Australia; and Department of Cell and Molecular Biology,
Feinberg School of Medicine, Northwestern University, Chicago, Illinois
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I. General Introduction
II. Factor XIII-A
A. General overview and protein expression
B. Factor XIII mouse models
C. Hemostasis and thrombosis
D. Tissue remodeling in cancer and wound repair
III. Skin and Hair Transglutaminases: TG1, TG3, and TG5
A. General overview and protein expression
B. TG1 mouse models
C. Lamellar ichthyosis
IV. Transglutaminase 2
A. General overview and protein expression
B. TG2 mouse models
C. TG2 and erythrocytes
D. Gluten sensitivity diseases
E. Cataracts
F. Inflammation and tissue remodeling/repair
G. Cancer
H. TG2, FXIII-A, bone, and osteoarthritis
I. Cardiovascular disease
J. Neurodegenerative disorders
K. Diabetes
V. Protein 4.2
A. General overview and protein expression
B. Protein 4.2 mouse model
C. Hereditary spherocytosis
VI. Conclusions and Future Directions
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Iismaa SE, Mearns BM, Lorand L, Graham RM. Transglutaminases and Disease: Lessons From Genetically
Engineered Mouse Models and Inherited Disorders. Physiol Rev 89: 991–1023, 2009; doi:10.1152/physrev.00044.2008.—
The human transglutaminase (TG) family consists of a structural protein, protein 4.2, that lacks catalytic activity, and
eight zymogens/enzymes, designated factor XIII-A (FXIII-A) and TG1-7, that catalyze three types of posttranslational
modification reactions: transamidation, esterification, and hydrolysis. These reactions are essential for biological
processes such as blood coagulation, skin barrier formation, and extracellular matrix assembly but can also
contribute to the pathophysiology of various inflammatory, autoimmune, and degenerative conditions. Some
members of the TG family, for example, TG2, can participate in biological processes through actions unrelated to
transamidase catalytic activity. We present here a comprehensive review of recent insights into the physiology and
pathophysiology of TG family members that have come from studies of genetically engineered mouse models and/or
inherited disorders. The review focuses on FXIII-A, TG1, TG2, TG5, and protein 4.2, as mice deficient in TG3, TG4,
TG6, or TG7 have not yet been reported, nor have mutations in these proteins been linked to human disease.
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I. GENERAL INTRODUCTION
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FIG. 1. Transglutaminase tertiary structure, protein domains, and
genomic organization. A: three-dimensional ribbon structure of the compact, inactive GDP-bound form (37, 162) and the expanded irreversible
peptide inhibitor-bound form of TG2 (224). The four structural domains
of the protein (␤-sandwich, core, and barrels 1 and 2) are color-coded as
in Fig. 1B. NH2 and COOH termini are labeled. GDP and the reactive
gluten-peptide mimic inhibitor Ac-P(DON)LPF-NH2 are shown as black
lines. Although only TG2 (38, 118, 121, 122), TG4 (262), and TG5 (54)
have been shown to bind GTP, the crystal structures of all human TGs
solved in the absence of calcium [FXIII-A (305), TG2 (37, 162), TG3 (11)]
assume the same compact conformation, in which the TG active site is
buried. B: dotted lines indicate exons encoding structural domains of the
protein, with the relative location of the transition-state-stabilizing Trp,
and active site Cys, His, and Asp shown. Genes encoding FXIII-A
(F13A1) and TG1 (TGM1) consist of 15 exons (numbered) and 14
introns; genes encoding TG2-7 (TGM2-7) and protein 4.2 (EPB4.2) consist of 13 exons (numbered) and 12 introns. In F13A1 and TGM1, exon
1 is noncoding, exon 2 encodes an NH2-terminal pro-peptide that is
cleaved upon activation of TG activity, and exons 10 and 11 are separated by an intron that is not present in TGM2-7 and EPB4.2.
donor is H2O and the -NH2 group on the acceptor protein
glutamine side chain is replaced with an -OH group to
form a glutamate, or isopeptide cleavage, which involves
a H2O molecule acting as the donor, leading to scission of
the isopeptide bond cross-linking two proteins.
The different TGs generally exhibit remarkable substrate specificity. Although the same protein substrate can
be recognized by distinct TGs, the enzymes have different
affinity and/or specificity toward the reactive glutamines/
lysines. The covalent isopeptide cross-link is stable and
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The human transglutaminases (TGs) are a protein
family consisting of a structural protein, protein 4.2, that
lacks catalytic activity, and eight zymogens/enzymes designated factor XIII-A (FXIII-A), transglutaminase (TG) 1,
TG2, TG3, TG4, TG5, TG6, and TG7, that catalyze a variety
of Ca2⫹- and thiol-dependent posttranslational proteinmodifying reactions. All TG family members are comprised of four sequential and structurally distinct domains
(an NH2-terminal ␤-sandwich, an ␣/␤ catalytic core, and
two COOH-terminal ␤-barrel domains) that assume a compact conformation in the absence of calcium (Fig. 1A). Two
family members, FXIII-A and TG1, have an additional
NH2-terminal pro-peptide sequence that may be cleaved
to generate the active enzyme (Fig. 1B). A remarkably
large conformational change, from the compact form to
an extended ellipsoid structure that exposes the TG active
site, accompanies activation of TG2 (37, 224) and likely
other TG family members (Fig. 1A). Central to TG enzymatic activity is the active site catalytic triad consisting of
a cysteine, histidine, and aspartate residue, and a conserved tryptophan that stabilizes the transition state: all
four residues are essential for catalysis (Fig. 1B) (92, 116,
158, 187, 197, 218). The catalytically inactive member,
protein 4.2, is evolutionarily related to the other TGs, as is
evident from its high degree of sequence conservation
(37–51% overall sequence similarity). However, none of
the four residues critical for catalysis is conserved in
protein 4.2.
Although protein cross-linking is the best-known catalytic reaction of these enzymes, they mediate at least five
posttranslational modification reactions that can be divided into three types: transamidation, esterification, and
hydrolysis. All five reactions involve a glutamine-containing protein or peptide as the first, acyl or acceptor substrate, which reacts with the active site cysteine to form a
covalently linked ␥-glutamylthioester, the acylenzyme intermediate, with ammonia being released as a by-product
(Fig. 2). This initial acylation step is followed either by a
direct attack by water (hydrolysis) or by the binding of a
second substrate, such as an amine (transamidation reaction) or an alcohol (esterification), to cleave the thioester
bond (the deacylation step) with generation of the hydrolyzed, cross-linked, or esterified product, respectively (for
review, see Ref. 168). Transamidation reactions result in
either protein cross-linking, in which a glutamine residue
is cross-linked via an N␧-(␥-glutamyl)lysine isopeptide
bond to a lysyl residue; amine incorporation, in which a
primary amine is incorporated onto a glutamine side
chain of the acceptor protein; or acylation, in which a
lysine side chain in a donor protein is acylated. Esterification, on the other hand, results in fatty acid modification of an acceptor-protein glutamine side chain, whereas
hydrolysis results in either deamidation, in which the
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FIG. 2. Reaction cycle for TG-catalyzed posttranslational modifications. The active site Cys and His form a thiolate-imidazolium ion pair.
Binding of the Gln-containing substrate 1 enables attack of the ␥-carboxamide group in the substrate by the thiolate. The reaction proceeds through
oxyanion intermediate 1, which is stabilized by H-bonding both to the backbone nitrogen of the active site Cys and to the N␧1 nitrogen of the
transition-state-stabilizing Trp. In the ensuing acylation step, NH3 is released as the acylenzyme intermediate is formed. A high specificity for the
second substrate is manifested in a saturable complex between substrate 2 and the acylenzyme intermediate. Nucleophilic attack by the amino group
of substrate 2 leads to formation of oxyanion intermediate 2, which is again stabilized by H-bonding interactions to both the active site Cys and the
transition-state-stabilizing Trp. In the final deacylation step, cross-linked product is released and the TG is regenerated. [Adapted from Iismaa et al.
(116).]
resistant to proteolysis, thereby often increasing the resistance of the resulting supramolecular structure to proteolytic degradation. The reactions catalyzed by TGs are
thus essential for biological processes such as blood coPhysiol Rev • VOL
agulation, skin barrier formation, and extracellular matrix
assembly. TGs also contribute to the pathophysiology of
blood and skin disorders and various inflammatory, autoimmune, and degenerative conditions.
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IISMAA ET AL.
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type) leads to changes between the lines after five generations (⬃18 mo of breeding) due to genetic drift. Furthermore, continued sequential sibling matings lead to the
generation of substrains with substrain-specific spontaneous mutations then becoming fixed within the lines (268,
278). To distinguish subtle effects of a gene deletion/
transgene from effects of other genes within the background of the strain, it is, therefore, essential to compare
animals in which differences in the genetic background
have been eliminated as a variable in the experiment
(253). This is best done in transgenic mice by back-crossing to the inbred strain used to create the mouse, and in
gene deletion (knockout) mice by back-crossing to an
inbred strain, for 10 or more generations. Homozygous
knockout and wild-type littermate controls should only be
generated from heterozygous crosses.
Based on the above considerations, we review here
recent insights into the physiology and pathophysiology
of members of the TG family that have come from studies
of genetically engineered animal models and/or inherited
disorders. The review focuses on FXIII-A, TG1, TG2, TG5,
and protein 4.2, as mice deficient in TG3, TG4, TG6, or
TG7 have not yet been reported, nor have mutations in
these proteins been linked to human disease. The major
conclusions that can be drawn from consideration of the
available studies are as follows: the clotting disorders in
FXIII-deficient patients are phenocopied in FXIII-A-deficient mice, demonstrating the integral and unique extracellular cross-linking role of plasma FXIIIa in blood coagulation (see sect. II). The intracellular cross-linking
roles unique to TG1 or TG5 in skin barrier formation are
evident from TG1- or TG5-deficient patients presenting
with lamellar ichthyosis or acral peeling skin syndrome,
respectively, and from TG1-deficient mice (see sect. III).
Studies with TG2-deficient mouse models indicate a pleiotropic role for TG2 in pathophysiology, with demonstrated involvement in cataract development, gluten sensitivity diseases, neurodegeneration, and tissue remodeling/repair associated with heart, liver, and kidney disease,
cancer, and bone development (see sect. IV). The only TG
other than TG2 with manifest pleiotropy is FXIII-A; the
roles of FXIII-A and TG2 are often complementary, as
observed for bone development, but can also be opposing, as evidenced by cancer progression in knock-out
mouse models (see sects. II and IV). Finally, studies with
protein 4.2-deficient mice and inherited mutations associated with hereditary spherocytosis indicate a noncatalytic, intracellular structural role for protein 4.2 in ion
transport across the RBC membrane (see sect. V). The key
concepts that have emerged from these studies of genetically engineered animal models and clinical inherited
disorders, and areas of future investigation, are discussed
(see sect. VI).
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In addition to these well-studied enzymatic actions,
some members of the TG family participate in a plethora
of other biological processes through actions unrelated to
their transamidase catalytic activity (for review, see Ref.
168). For example, TG2 (38, 118, 121, 122), TG4 (262), and
TG5 (54) bind and hydrolyze GTP: GTP binding causes a
transition to the compact, inactive conformation and inhibition of TG activity (37, 162). To date, however, only
TG2 has been shown to utilize this function in its role as
a high-molecular-weight G protein (Gh) involved in signaling by certain G protein-coupled receptors (59, 202, 216,
300). FXIII-A (293) and TG2 (16, 167, 283, 311) also function as adaptor proteins to facilitate matrix interactions
during cell adhesion. Finally, TG2 has also been reported
to act as a serine/threonine kinase (190 –192), a protein
disulfide isomerase (110), and an extracellular ligand for
the orphan GPCR, GPR56, which is involved in tumor
suppression (117, 303), although involvement of these
latter functions in physiology and/or disease remains unclear.
Although the biological actions and enzymology of
the mammalian TG family have been considered in previous reviews (e.g., Refs. 103, 168), much has been learned
recently, particularly about TG2, from studies of genetically engineered animal models. In contrast to in vitro
experiments and cell culture models that are useful for
dissecting protein functions, such studies allow the integrated actions of proteins to be evaluated in the setting of
diverse cellular contexts and inputs and, while complicated, are frequently the only avenue for elucidating the
full array of activities of a protein of interest. Moreover, if
they model human diseases caused by an apparent inherited gene mutation, they can be a powerful tool for confirming disease causation, as well as for allowing the
evaluation of disease mechanisms and the therapeutic
potential of novel drugs and therapeutic strategies. Furthermore, where no inherited disorder has been identified, due, for example, to redundancy or to mutations
causing an embryonic lethal phenotype, animal models
involving conditional gene inactivation may be the only
approach for determining the physiological role of a protein of interest.
Caution, however, is required in performing animal
studies, as poor animal husbandry practices and/or the
use of nonlittermate or inappropriate background strain
controls can confound the interpretation of experimental
results. Thus inherent genetic differences that exist among
the commonly used mouse strains can influence physiological responses [e.g., sensitivity to Fas-mediated cell death
(212), insulin secretory function in response to a high-fat
diet (19), inflammatory cell recruitment (302), and postinfarct ventricular rupture (94)]. Moreover, a sequential series
of sibling matings within lines that have become physically
separated (e.g., homozygous knockout crossed with homozygous knockout, and wild-type crossed with wild-
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
II. FACTOR XIII-A
A. General Overview and Protein Expression
B. Factor XIII Mouse Models
Mixed strain [SVJ129-C57BL/6-Swiss albino-129O1aCBACa (156) or SVJ129-C57BL/6J-NIH Black Swiss (260)]
FXIII-A-deficient mice were developed by replacement of
exon 7 of the F13A1 gene (which encompasses the catalytic active site of FXIII-A) with a neomycin resistance
gene (Fig. 1B). Plasma FXIII-A activity was reduced to
50% in heterozygous mice and was absent in homozygous
mice (156, 260). Plasma levels of FXIII-B were also decreased (to ⬍20% of wild-type levels) in FXIII-A⫺/⫺ mice,
indicating that both FXIII-A and -B are protected in the
A2B2 complex in the circulation (260). Spontaneous hemorrhage, including hemothorax, hemoperitoneum, subcutaneous bleeding, and early abortion contributed to reduced survival of pregnant female FXIII-A⫺/⫺ mice (156,
260). Although heart structure and function were normal
in FXIII-A⫺/⫺ mice, a gender-specific effect of widespread
fibrosis with hemosiderin deposition and reduced survival
of male FXIII-A⫺/⫺ mice was observed (261).
Mixed strain (SVJ129-C57BL/6J) FXIII-B-deficient
mice (260) have been developed by replacement of exons
1 and 2 of the F13B gene (which encompass the translation initiation codon and signal peptide) with a neomycin
resistance gene. Plasma FXIII-B was absent in homozygous mice and, although steady-state FXIII-A mRNA levPhysiol Rev • VOL
els were unchanged, FXIII-A protein and activity were
only ⬃1–20% of wild-type levels. Unlike FXIII-A⫺/⫺ mice,
survival of FXIII-B⫺/⫺ mice did not differ from that of
wild-type controls (261), and no female FXIII-B⫺/⫺ mice
died during pregnancy (260).
C. Hemostasis and Thrombosis
The pivotal extracellular role of pFXIII in hemostasis
is well established. In human blood coagulation, the activated form of pFXIII (designated pFXIIIa or pFXIII-A2*)
stabilizes fibrin matrix assembly during clot formation by
catalyzing the covalent linkage of fibrin monomers at
selected locations [a process akin to spot-welding (164);
Fig. 3]. In addition, pFXIIIa enhances incorporation of
␣2-plasmin inhibitor into the clot network (238). Though it
does not influence clotting and primary bleeding times,
the pFXIII system is recognized as an integral part of the
normal coagulation process, essential for establishing a
properly functioning fibrin matrix that provides the clot
with the necessary structural stiffness and plasticity for
wound closure, and also with sufficient resistance against
lytic enzymes (Fig. 3). The FXIII-B subunits help with
binding the pFXIII-A2B2 zymogen to fibrinogen and, importantly, also act as a brake in the thrombin-catalyzed
cleavage of the zymogen and hence control the conversion of pFXIII to pFXIIIa. Timing of the operation of the
pFXIII system is regulated by unique “feed-forward” control mechanisms. Fibrin accelerates thrombin-catalyzed
activation of the pFXIII zymogen by about two orders of
magnitude; binding to fibrin allows for the rapid dissociation of subunits to take place at the physiological Ca2⫹
concentration of plasma. Also, the prior end-to-end assembly of fibrin units boosts the reactivity of cross-linking
sites at ␣COOH-terminal sites, by ⬃10-fold (164).
In the explosive process of blood clotting, activation
of pFXIII is a multistep process: thrombin-catalyzed release of a 34-residue activation peptide from the NH2
termini of the A subunits by limited proteolysis is critical
for loosening their attachment from the B subunits, but
the catalytic Cys in the active center of the pFXIII-A2
enzyme (shown as pFXIII-A2* in Fig. 3) becomes accessible only as a consequence of the Ca2⫹ and fibrin-assisted
separation from the B subunits. The cross-linking activity
of pFXIII can also be activated without prior thrombin
cleavage, but the A2B23 A2⬘⫹B2 dissociation inherent in
this type of activation requires a much higher than physiological concentration of Ca2⫹. The next step in the
process can take place at low concentrations of Ca2⫹ and
is a facile conformational change from the free pFXIII-A2⬘
to an enzymatic form that has the same accessibility of its
active center Cys (determined by titration with the alkylating agent, iodoacetamide) as that of pFXIII-A2*. However, since its tertiary structure differs from pFXIII-A2* by
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FXIII, as a zymogen, has both extracellular and intracellular functions. In plasma, it is thought to circulate as
a heterotetrameric ensemble (plasma coagulation factor
XIII, pFXIII-A2B2 or fibrin stabilizing factor), where the A
subunit (⬃83 kDa, encoded by the F13A1 gene on human
chromosome 6p24 –25; Fig. 1B) belongs to the TG family
of proteins and the regulatory/carrier B subunit (⬃80 kDa,
encoded by the F13B gene on chromosome 1q31-32.1 and
synthesized in the liver and kidney), is related to the
“small consensus” or “sushi” repeat protein family (159).
The richly sialylated B subunit protects the A subunit in
the circulation. This is evident from the fact that a human
null mutation of the B subunit was associated with A
subunit deficiency (237). Cellular factor XIII, cFXIII, is
thought to exist as an A2 homodimer (cFXIII-A2) and is
found in the cytoplasm of megakaryocytes/platelets (up
to 50% of the total FXIII-A activity in blood is in platelets;
Ref. 5). Platelets have been reported to also contain low
levels of TG2 (228). FXIII-A can be detected in macrophage populations associated with wound healing and
tumor progression (288) and in other cell types such as
chondrocytes and osteoblasts (209 –211). The role of
FXIII-A in bone development is detailed in section IVF.
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the presence of the NH2-terminal activation peptide, the
enzyme generated by the thrombin-independent pathway
is denoted as FXIII-A2°. This also represents the active
form of the enzyme found in platelets, monocytes, and
other cells (cFXIIIa), where the zymogen exists as free A2
homodimers without the carrier B subunits; A2 becomes
activated to A2° by a relatively small elevation of intracellular Ca2⫹ concentration (Fig. 3). Although both A2* and
A2° have the same steady-state kinetic constants on small
test substrates, they seem to behave differently in reactions with larger protein substrates.
A relatively common single nucleotide polymorphism
in F13A, leading to replacement of Val-34 with Leu in the
activation peptide, results in faster FXIII-A activation due
to accelerated thrombin cleavage of the activation peptide (22). This Val34Leu polymorphism has been associated with improved wound healing (99) and survival after
myocardial infarction (98), but also an increased risk of
oral cancer (294).
Several hundred autosomal, recessively inherited cases of
human FXIII deficiency are known worldwide (for a comprehensive list of FXIII-A mutations, see Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/omim). Most are
due to loss-of-function missense mutations in F13A that,
on account of transcriptional or folding problems, prevent
the production of the functionally competent A subunits
of the zymogen. However, as indicated above, in a small
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number of cases, the absence of the factor in the circulation is due to mutation in F13B that results in a failure to
produce the carrier B subunits, without which the A
subunits do not survive in the circulation (126, 147, 237).
In either case, in the absence of FXIIIa-mediated crosslinking activity being generated during the coagulation
process, the hemostatic plug fails on account of its mechanical weakness and increased susceptibility to lysis.
Both FXIII-A (156, 260) and FXIII-B knockout mice (260)
phenocopy human FXIII deficiency, showing decreased
fibrin cross-linking in plasma and, consequently, plasma
clots that are similarly less stiff and more easily lysed than
controls. Administration of recombinant FXIII-B into
FXIII-B⫺/⫺ mice accelerated fibrin cross-linking in plasma
and assisted maintenance of plasma FXIII-A levels (260).
Most FXIII-deficient patients are diagnosed soon after birth as they display prolonged umbilical cord bleeding that continues for a day or more, although in a few
cases the genetic defect in some individuals may remain
undetected until quite late in life. Bleeding phenotypes
vary greatly from very mild to life-threatening (intracranial hemorrhage in ⬃30%; Ref. 170). Judicious replacement therapy with FXIII concentrates administered once
a month can mitigate and even prevent the bleeding episodes. FXIII-A⫺/⫺ mice (156, 260) exhibit a relatively mild
bleeding predisposition with somewhat prolonged tail-tip
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FIG. 3. Pathways of FXIII-A activation and the clotting of fibrinogen in blood plasma. The FXIII zymogen exists in plasma as the pFXIII-A2B2
heterotetramer and as the cFXIII-A2 homodimer in cells. In the physiological pathway of clotting in plasma, thrombin has the dual role of controlling
the rate of fibrin production from fibrinogen and the rate of activation of the plasma FXIII zymogen by cleavage of ArgGly peptide bonds in the
NH2-terminal domains of fibrinogen and the A subunits of pFXIII. Removal of the activation peptide from the A subunits converts pFXIII-A2B2 to
pFXIII-A2⬘B2, and active pFXIIIa (pFXIII-A2*) is generated by a conformational change following dissociation from the carrier subunits. These
reactions occur in the plasma milieu of 1.5 mM Ca2⫹. The fibrin substrate exerts major regulatory influences on the formation of the A2* enzyme
at every step on the way. In the absence of pFXIIIa, the fibrin clot is soluble in 30% urea or in 1% monochloroacetic acid and can be readily lysed
by plasmin. However, the pFXIIIa-catalyzed covalent ligation of the clot by N␧(␥-glutamyl)lysine bridges renders it insoluble in these reagents and,
especially with the concomitant incorporation of the ␣2 plasmin inhibitor (␣2PI) into the network, more resistant to lysis. Activation of platelets and
monocytes, with concomitant influx of Ca2⫹, brings about the conversion of cFXIII-A2 to cFXIII-A2°, causing cross-linking of cell proteins. Platelets
and other cells have also been shown to express FXIII-A2 or A2° on their surfaces.
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Physiol Rev • VOL
FXIII-A⫺/⫺, and TG2⫺/⫺/FXIII-A⫺/⫺ double-knockout mice
are clearly needed.
In women, habitual abortion, as in afibrinogenemia
and in some cases of hypodysfibrinogenemia, is a frequent manifestation of FXIII deficiency (170). Similarly,
mixed strain (SVJ129-C57BL/6-Swiss albino-129O1aCBACa) FXIII-A⫺/⫺ mice are fertile, but reproduction is
greatly impaired (148), with female knockout animals
frequently developing overt genital bleeding around the
10th day of gestation (regardless of the genotype of the
male mating partners), resulting in fetal abortion. About
50% of pregnancies result in maternal death. Because the
occurrence and severity of bleeding events, and the number of abortions, varies among the pregnant females, it is
likely that hemorrhage in these animals is due to chance
rupture of blood vessels in the placenta. Thus FXIII-A also
functions in the maintenance of tissue integrity to allow a
normal pregnancy, although its mechanism of action in
this regard is yet to be delineated.
D. Tissue Remodeling in Cancer and Wound Repair
Tissue remodeling is a complex process involving
temporarily overlapping phases that include inflammation, tissue formation and remodeling, and the interaction
of platelets, macrophages, fibroblasts, and endothelial
cells. FXIIIa, like TG2 (see sect. IV, F and G), is likely
involved in several steps of the remodeling processes
involved in cancer and tissue repair, including cell adhesion and migration, clot formation, and angiogenesis.
FXIII-A-deficient mice have recently been used to
investigate the role of FXIIIa in tumor growth and metastasis. In contrast to TG2⫺/⫺ mice (see sect. IVG), tumor
size was comparable between mixed strain (97% C57BL/
6J-3% SVJ129) FXIII-A-deficient and wild-type mice (215).
Significantly, hematogenous metastasis to lung and liver
of either intravenously or intradermally injected tumor
cells was diminished in FXIII-A⫺/⫺ relative to wild-type
mice, whereas lymphatic metastasis to lymph nodes of
intradermally injected tumor cells was unaffected. Analysis of the early fate of circulating tumor cells indicated
equivalent initial localization of tumor cells to the lungs
within 30 min of injection, but reduced survival of these
cells after 26 h in FXIII-A⫺/⫺ mice due to increased clearance by natural killer cells (215). Thus, although FXIII is
not required for the growth of established tumors or the
initial adhesion of circulating tumor cells, it supports
metastatic spread by limiting natural killer cell function.
The mechanism involved has not yet been established;
however, a plausible hypothesis may involve tumor cell
evasion of natural killer cells through FXIII-mediated tumor cell-associated matrix cross-linking.
Impaired wound healing is a fairly common problem
in individuals with hereditary FXIII deficiency (see Refs.
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bleeding times, whereas other laboratory values of hemostasis are normal.
Platelets activated simultaneously with collagen and
thrombin comprise a subpopulation of activated platelets
that likely contribute significantly to thrombotic processes because they become “coated” with a number of
procoagulant proteins, including factor V, fibrinogen, fibronectin, thrombospondin, and von Willebrand factor
(64). Many of these procoagulant proteins are posttranslationally modified by transamidase-mediated conjugation
with serotonin (65), a process that enhances their procoagulant activity (275). Although the formation of a polymer or of ␥:␧ isopeptides in these platelet reactions has
not been shown, inhibition of coated-platelet formation,
by an anti-FXIII-A antibody and by competitive substrate
inhibition with dansylcadaverine, suggested a role for
FXIII-A in coated-platelet formation (65). However, platelets from mixed strain (SVJ129-C57BL/6-Swiss albino129O1a-CBACa) FXIII-A⫺/⫺ mice showed unaltered coatedplatelet formation relative to FXIII-A⫹/⫺ littermates (128).
The reason for these discrepant findings is unclear and
may reflect differences between human and mouse platelets in some other component, such as TG2. Thus murine
FXIII-A⫺/⫺ platelet lysates had higher transamidase activity than platelet lysates from wild-type C57BL/6 mice,
despite the absence of FXIII-A expression (128), suggesting that TG2 (or some other TG) may compensate for the
absence of FXIII-A, akin to bone development (see sect.
⫺/⫺
IVH). Studies with both TG2
and TG2⫺/⫺/FXIII-A⫺/⫺
double knockout mice, if viable, would help further delineate the respective roles of these transglutaminases in
coated-platelet formation.
Serotonin has also been demonstrated to posttranslationally modify small GTPases by transglutaminase-mediated cross-linking, during platelet activation. As a result,
the small GTPases are constitutively activated, leading to
irreversible aggregation and platelet ␣-granule release
(301). These findings stem from experiments with mixed
strain (SVJ129-C57BL/6) tryptophan hydroxylase-deficient (TPH) mice, in which the concentration of peripheral serotonin, as found in platelets, is greatly reduced.
TPH⫺/⫺ mice exhibit impaired hemostasis with prolonged bleeding time. Although neither the ultrastructure nor the in vitro aggregation properties of serotonin-deficient platelets differ from normal, their adhesion
in vivo is greatly reduced due to a blunted secretion of
adhesive ␣-granular proteins, such as the multimeric form
of the von Willebrand factor which, under the high shear
rates existing in the circulation, is essential for platelet
adhesion. Thus normal secretion of ␣-granules depends
on the functioning of a transglutaminase-regulated signaling process requiring cytoplasmic Ca2⫹ and serotonin.
Again, it is unclear if FXIII-A is involved or if other TGs,
such as TG2, also play a role. Further studies with TG2⫺/⫺,
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FIG. 4. FXIIIa cross-link-activated receptor signaling. FXIIIa-catalyzed extracellular cross-linking of ␤3 integrin to VEGFR-2 results in
VEGFR-2 activation and angiogenesis. FXIIIao-catalyzed intracellular
dimerization of AT1 receptors enhances AT1 receptor signaling in hypertensive patients and results in increased adhesiveness of monocytes to
endothelial cells.
Calcium ionophore activation of the cFXIII-A2 zymogen in normal human monocytes, in conjunction with
stimulation by angiotensin II, caused covalent dimerization of the angiotensin II type 1 (AT1) receptor (3). The
enzymatic cross-linking, which was inhibited by the TG
inhibitors dansylcadaverine or cystamine, or by the AT1
receptor antagonist losartan, involved residue Gln-315 of
the COOH-terminal intracellular tail of the receptor and
led to its sustained upregulation, while enhancing also the
adhesion of monocytes to endothelial cells (Fig. 4). Crosslinked AT1 receptor dimers are characteristically found in
monocytes of patients with essential hypertension, but
are absent in monocytes of FXIII-deficient individuals.
Treatment with the angiotensin converting enzyme inhibitor captopril, (3) or the AT1 receptor antagonist eprosartan (80), diminished the adhesiveness of monocytes of
hypertensive patients. Cross-linked AT1 receptor dimers
were also found in monocytes of dyslipidemic pure strain
(C57BL/6J) ApoE⫺/⫺ mice, which are prone to excessive
aortic root plaque formation due to enhanced monocyte
adhesion (3). Captopril treatment significantly decreased
the amount of cross-linked AT1 receptor dimers and suppressed monocyte cFXIII-A2 activity (3). These findings
provide the molecular framework for explaining the connection between hypertension and vascular diseases. In a
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69, 170 for review) and may impact on recovery following
myocardial infarction (200). FXIIIa stimulates endothelial, monocyte, and fibroblast cell proliferation and migration, while inhibiting apoptosis (66, 70). In models of
blood vessel tube formation developed using human umbilical vein and microvascular endothelial cells, FXIIIa
produced dose-dependent enhancement of endothelial
cell arrays and, in a rabbit cornea model, injection of
FXIII-A caused neovascularization (70). In murine models
with neonatal heterotopic cardiac allograft transplant and
Matrigel implant, the number of new vessels and percentage of heart beating areas were significantly greater following FXIII-A injection into the allografts than in controls, and by incorporating FXIII-A into the Matrigel, the
number of blood vessels was almost the same as obtained
by incorporation of the well-known proangiogenic factor
basic fibroblast growth factor (bFGF) (67). The angiogenic activity of FXIII-A also promotes the healing process with biomaterials, such as in experimental rat tibial
bone defects filled with a nanoparticulate hydroxyapatite
paste (137). This angiogenic effect is mediated by phosphorylation and activation of the endothelial cell-specific
receptor for vascular endothelial growth factor, VEGFR-2,
leading to upregulation of the transcription factors Egr-1
and c-Jun (66, 68). c-Jun downregulates mRNA expression of the platelet-secreted angiogenesis inhibitor thrombospondin 1 (66, 70) and secretion of the protein (70) via
Wilm’s tumor-1 (68). Remarkably, key to the activation of
VEGFR-2 seems to be FXIIIa-catalyzed extracellular
cross-linking of VEGFR-2 to the ␤3 subunit of integrin
␣v␤3 (68), an integrin that is highly expressed by activated
endothelial and tumor cells and plays a critical role in
angiogenesis (296) (Fig. 4). Monocyte/macrophage FXIIIa
may also contribute to inward remodeling of small arteries in response to a reduction in blood flow (31).
Mixed strain (SVJ129-C57BL/6-Swiss albino-129O1aCBACa) FXIII-A-deficient mice subjected to 3-mm skinpunch biopsies exhibited a delay in wound healing relative to wild-type CBA mice, which was restored by intraperitoneal injection of FXIII concentrate every 3 days
(124). FXIII-A-deficient mice (background strain not specified) also had increased incidence of fatal left ventricular
rupture, compared with wild-type CBA mice, following
myocardial infarction (199). This increased rupture was
associated with an attenuated inflammatory response, impaired collagen synthesis, and enhanced ECM degradation. Daily intravenous FXIII-A replacement therapy improved survival, increased neutrophil migration, and reduced ECM degradation, but did not restore collagen
synthesis and resulted in thinner infarct scars and larger
left ventricles than in wild-type or untreated FXIII-A-deficient mice (199). This inability to completely rescue
FXIII-A deficiency by extracellular reconstitution may reflect an important intracellular role for platelet or monocyte/macrophage cFXIII.
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
general sense, they also highlight the role played by
FXIIIa in amplifying some receptor-mediated signaling
processes (Fig. 4). As presented above, we have examples
for two different modes of amplification of such “crosslink-activated receptor signaling” (CLARS): the cross-linking of VEGFR-2 is likely catalyzed by FXIIIa from outside
of the cell (CLARS1), whereas that of AT1 receptor is by
the intracellular enzyme (CLARS2).
III. SKIN AND HAIR TRANSGLUTAMINASES:
TG1, TG3, AND TG5
The multilayered epidermal surface of the skin provides a flexible, physical, and chemical barrier to the
external environment. It is continually regenerated by the
differentiation of keratinocytes into corneocytes, which
occurs during their passage from the innermost proliferative (basal epidermal) layer through the spinous and
granular layers. Here, daughter cells differentiate to synthesize and then cross-link cornified cell envelope (CE)
structural proteins. Corneocytes deposit beneath their
plasma membrane a 15-nm-thick CE consisting of a 5-nmthick cross-linked lipid layer that coats the exterior and is
covalently attached to a 10-nm-thick highly cross-linked
protein scaffold. TG2 is expressed primarily in the basal
layer of the epidermis (7), TG1 and TG5 are present in the
spinous and granular layers, and TG3 seems to be confined to the upper granular layer (52).
In hair follicle development, elongated keratinocytes
of the hair germinal follicle, visible as an epidermal thickening, grow into the dermis to form a hair peg. The base
of the hair peg undergoes bulblike enlargement to form
the dermal papilla, concomitant with the differentiation of
the hair shaft, development and elongation of the inner
root sheath, and differentiation of the outer root sheath
and sebaceous gland. The hair follicle elongates through
the deep subcutis at an angle of 40° to the epidermis to
reach the subcutaneous muscle layer, and the hair shaft
emerges through the epidermis (217). The only TG
present in the hair germinal follicle is TG2. During its
development, TG1, TG2, and TG3 are present in the inner
cells of the hair peg. TG1 remains restricted to the inner
root sheath and the inner cells of the dermal outer root
sheath; TG3 becomes restricted to the hair shaft, while
TG5 expression overlaps with that of involucrin in the
inner root sheath, the outer root sheath, and the hair shaft
(284). CE formation is observed throughout the inner root
sheath, in the inner cells of the dermal outer root sheath,
and in the hair canal (17).
The molecular events of CE development are believed to be almost identical in the epidermis and hair
follicle (17). TG2 plays a role in stabilization of the derPhysiol Rev • VOL
moepidermal junction (7) but is not involved in cornification. TG1, TG3, and TG5 have distinct, yet complementary, roles in cross-link formation during CE assembly.
For example, in the spinous layer of the epidermis, CE
formation is likely initiated by TG1- and TG5-mediated
cross-linking of envoplakin and periplakin to the desmosome (55). In the granular layer, loricrin, the major CE
protein, and small proline-rich proteins are cross-linked
by TG3 to form oligomers and in the final reinforcement
stages are cross-linked to the CE by TG1 (56). TG1 and
TG3 cross-link at different sites (56). Formation of the
lipid envelope occurs by TG1-mediated cross-linking of
lipids (␻-hydroxyceramides) to already cross-linked proteins such as envoplakin, periplakin, and involucrin (206).
1. TG1
TG1 (encoded by the gene TGM1 on human chromosome 14q11.2) is synthesized as an inactive zymogen of
106 kDa (Fig. 1B). It is expressed at low levels in proliferating keratinocytes and is progressively induced during
keratinocyte differentiation (265), concomitant with the
expression of keratinocyte differentiation regulator, tarazotene-induced protein 3 (TIG3), which regulates terminal
differentiation by activating TG1 (271, 272). TG1 is also
expressed in the adherens junctions of epithelial cells in
lung, kidney, and liver (113) and in myocardial microvascular endothelial cells (35). The majority of keratinocyte
TG1 is bound to the plasma membrane in proliferating or
differentiating cells via NH2-terminal myristate or palmitate linkages, respectively (266). During terminal differentiation, a significant fraction of the membrane-bound
TG1 zymogen is proteolytically processed into a highly
active 10/67/33-kDa complex (265) responsible for most
of the TG1 enzyme activity that not only cross-links CE
proteins, but also links the terminal (␻) hydroxyl group of
long-chain ␻-hydroxyceramides onto CE proteins (206).
2. TG3
TG3 (encoded by TGM3 on human chromosome
20q11-12; Fig. 1B) is synthesized as an inactive 77-kDa
zymogen that is proteolytically processed by cathepsin L
(60) into an active 50/27-kDa complex (139). Trichohyalin,
a major structural protein of the hair follicle, is crosslinked predominantly by TG3 (280). To date, no mutations
in TGM3 have been linked to disease. A preliminary report
at the 9th International Conference on Transglutaminases
and Protein Cross-linking (Morocco, Sept 1– 4, 2007) detailed a curled structure of the fur and whiskers of
TG3⫺/⫺ mice, with irregularities in ultrastructure and increased protein extractability reflecting altered crosslinking of hair structural proteins (285).
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A. General Overview and Protein Expression
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3. TG5
TG5 (encoded by TGM5 on human chromosome
15q15.2; Fig. 1B) has a molecular mass of 81 kDa (6). Like
TG1 and TG3, activation of TG5 cross-linking activity may
require proteolytic processing (223). TG5 appears to associate with the vimentin intermediate filament network
in cultured keratinocytes that are undergoing epithelialmesenchymal transition (53). TG5 is also found in several
fetal and adult tissues; however, the exact cell type that
expresses this protein in these tissues is not yet known
(54). A loss-of-function mutation in TGM5 has been reported to cause acral peeling skin syndrome (57).
To gain insights into the regulation of TG1 expression, the TGM1 promoter has been analyzed in vivo using
transgenic mouse lines expressing reporter genes under
the control of various lengths of the human [2.5 kb (304),
2.2, 1.6, 1.1, and 0.3 kb (221)] or rabbit [2.9 kb (184)]
promoters or under the control of a 2.2-kb human TGM1
promoter fragment with mutated AP1 or CRE binding
sites (221). Correlation of transgene expression with that
of endogenous TG1 demonstrated that the 2.5-kb human
(304) and 2.9-kb rabbit TGM1 promoter (184) were sufficient to confer tissue- and terminal differentiation-specific expression. Like TG1 expression, the reporter was
upregulated by topical 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of adult tail skin (304). The minimal
length of human TGM1 promoter required for appropriate
expression was narrowed to slightly less than 1.6 kb and
shown to contain binding sites for the transcription factors AP1 and Sp1 (221). Transgenic reporter lines generated with the functional TGM1 promoter regions may be
useful to assess the in vivo effects of topical application of
chemicals or drugs on human TG1 promoter activation.
Functional TGM1 promoter regions may also be useful for
gene therapy or generation of conditional (tissue- and
terminal differentiation-specific) knockout mice via Cre/
loxP site-specific recombination.
Mixed-strain (SVJ129-C5BL/6) TG1-deficient mice (182)
were developed by replacement of exons 1–3 (encoding the
unique NH2-terminal membrane-anchoring domain of TG1)
with a neomycin resistance gene (Fig. 1B). TG1⫹/⫺ mice
were phenotypically indistinguishable from wild-type animals, whereas TG1⫺/⫺ neonates were smaller, often encased
in an inelastic translucent membrane reminiscent of that of
“collodion babies,” did not feed, became progressively dehydrated, and died within 4 –5 h after birth (182). Normal
development of the skin permeability barrier, which occurs around 16 days post coitum (dpc), was impaired in
TG1⫺/⫺ mice due to defects in CE formation (154). Similar
defective barrier functions were noted in stratified squamous epithelia of the tongue and forestomach, whereas
Physiol Rev • VOL
C. Lamellar Ichthyosis
Keratinization disorders or ichthyoses are characterized by thickened and scaly skin due to several distinct
defects. Lamellar ichthyosis is caused by defects in TG1
activity (114) that result in an inability to assemble both
the lipid envelope by ester bond formation as well as the
protein envelope by cross-linking of CE proteins (206).
Mutations in TGM1 have been identified due variously to
nonsense mutations, amino acid substitutions, or splice
site changes, which affect either enzyme activity or posttranslational proteolytic processing (reviewed in Ref. 140;
for a comprehensive list of TG1 mutations, see Online
Mendelian Inheritance in Man).
In X-linked ichthyosis, accumulation of cholesterol
sulfate, due to a deficiency in steroid sulfatase, inhibits
the capacity of TG1 to perform protein cross-linking and
ester linkage of ␻-ceramides, resulting in inhibition of
lipid-bound envelope formation. As a result, mechanical
stability of the intercorneocyte lipid layers is impaired,
leading to a lamellar ichthyosis-like phenotype (205).
Consistent with an exclusive role for TG1 in the final
reinforcement stages of CE assembly, TG1⫺/⫺ mice show
defective epidermal maturation late in embryonic development (16.5–17.5 dpc) that results in a drastic increase in
skin permeability and death from dehydration within a
few hours of birth (154, 182). Transplantation of TG1⫺/⫺
mouse skin to nude mice resulted in an ichthyosiform
phenotype with epidermal hyperplasia and marked hyperkeratosis. However, transepidermal water loss was comparable to that of grafted control skin, as was evident
when ichthyosiform thick scales were removed. Thus hyperkeratosis is an apparent compensatory response to
limit transepidermal water loss from the surface of the
TG1⫺/⫺ mouse skin (154).
IV. TRANSGLUTAMINASE 2
A. General Overview and Protein Expression
TG2 (encoded by TGM2 on human chromosome
20q11-12; Fig. 1B), a 74- to 80-kDa protein, is perhaps the
most intriguing member of the TG superfamily. This protein is found throughout the body due to its constitutive
expression in endothelial cells, smooth muscle cells, and
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B. TG1 Mouse Models
epithelial cells and adherens junctions in lung, liver, and
kidney were unaffected (154). Compared with control
grafts from wild-type mice, skin from TG1⫺/⫺ neonates
grafted onto nude mice showed a substantial delay in
epidermal regeneration following a full-thickness 10-mm
linear incision, thereby demonstrating the importance of
TG1 in skin wound healing (123).
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
B. TG2 Mouse Models
Like TG1, the Tgm2 promoter has been analyzed to gain
insights into control of murine TG2 expression using transgenic mouse lines expressing the Escherichia coli ␤-galactosidase (lacZ) reporter gene under the control of a 3.8-kb
5⬘-flanking promoter region of Tgm2 (pmTG3.8LacF)
(198). Correlation of transgene expression in embryos at
13.5 dpc with that of endogenous TG2 protein demonstrated that the 3.8-kb Tgm2 promoter region was sufficient to confer specific patterns of expression during
limb development. However, in contrast to expression
of endogenous TG2, no ␤-galactosidase activity was
detected in the liver or heart of transgenic embryos.
Thus, unlike TGM1, where a 1.6-kb promoter fragment
is sufficient to direct appropriate expression, the 3.8-kb
Physiol Rev • VOL
5⬘-flanking promoter region of the Tgm2 gene regulates
some, but not all, of the physiological expression of
TG2.
Transgenic mice that specifically overexpress rat
TG2 cDNA in the heart under the control of the murine
␣-myosin heavy chain promoter (256, 300, 312) have been
generated by two independent groups and have been used
to investigate the role of TG2 in intracellular signaling
pathways relevant to cardiac hypertrophy (see sect. IVH).
A transgenic mouse model overexpressing human TG2 in
neurons and heart has recently been generated using the
murine prion promoter (MoPrP) from the MoPrP.XhoI
expression transgenic vector (291). This mouse model
was created to study the role of TG2 in neurodegenerative
conditions (see sect. IVJ).
Two mixed strain (SVJ129-C57BL/6) knockout mouse
models for TG2 were developed simultaneously by different groups to evaluate the in vivo function of TG2. One
model was developed by replacement of part of exon 5
and all of exon 6 (exons that encode part of the catalytic
core domain) with a neomycin resistance gene (73), while
the other model was developed using the Cre/loxP system
with LoxP sites inserted into introns 5 and 8 for deletion
of exons 6 – 8 of the catalytic core (203) (Fig. 1B). Both
models showed absence of TG2 protein in homozygote
progeny. Although TG2 has been reported to either facilitate or attenuate apoptosis (reviewed in Refs. 88, 235),
TG2⫺/⫺ mice showed no obvious abnormal phenotype,
with no abnormalities of developmental apoptosis and no
difference in induced apoptosis of TG2⫺/⫺ thymocytes
and fibroblasts (73, 203). This, in itself, was surprising
given the ubiquitous expression of TG2. Nevertheless,
these mice have been useful in defining the role of TG2 in
pathology and under conditions of stress.
C. TG2 and Erythrocytes
The paradigm that an increase in intracellular Ca2⫹
concentration activates latent transglutaminases in many
cell types was first established for TG2 in human red
blood cells (RBCs) by the demonstration that TG2-catalyzed remodeling of membrane skeletal proteins via N␧(␥-glutamyl)lysine linkages was the immediate cause for
the apoptosis-like morphological and physical alterations in
these cells (175, 252). Competitive or direct inhibitors of
cross-linking activity offered effective protection against the
permanent abnormal shape changes and loss of membrane deformability (257). SDS-PAGE of ghosts from
Ca2⫹-treated RBCs revealed large polymeric clusters
ranging in molecular weight from ⬃1 ⫻ 106 to ⬃6 ⫻ 106
Da; some polymers appeared to be situated peripherally
to the inner leaflet (i.e., extractable by mild alkali), but a
major fraction was firmly anchored into the membrane
and could not be stripped away by alkali treatment. Since
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fibroblasts as well as in a number of organ-specific cell
types (9, 87, 89, 286, 287). TG2 is located in the ECM or at
the cell surface in association with the ECM (97) and also
intracellularly, where it is mostly cytosolic, but is also
found associated with the inner face of the plasma (38,
118, 121, 122) or nuclear membrane (254). TG2 is not
present in the mitochondria (151). The pathway(s) and
molecular mechanisms by which TG2 is externalized are
largely unknown.
The transamidase activity of TG2 plays an extracellular role in matrix stabilization, which is important in
wound healing, angiogenesis, and bone remodeling, and
an intracellular role, predominantly in the cross-linking of
proteins during apoptosis. TG2 has five reported functions in addition to its transamidase activity. These include GTPase activity and intracellular G protein signaling via the ␣1B/␣1D adrenergic receptors (59, 202), the TP␣
thromboxane A2 receptor (300), and the oxytocin receptor (216); an extracellular stabilizing function by being
able to form tight ternary TG2:fibronectin:collagen complexes (231, 292), and an adapter function to facilitate cell
adhesion to fibronectin by interacting directly with ␤1/
␤3/␤5 integrins (16, 311), with heparan sulfate chains of
the heparan sulfate proteoglycan receptor, syndecan 4
(283), or with the orphan G protein-coupled cell-adhesion
receptor GPR56 (117, 303). TG2 has also been reported to
possess intracellular serine/threonine kinase activity,
with insulin-like growth factor binding protein (IGFBP) 3,
p53 tumor suppressor protein, or histones (190 –192) as
substrates, as well as extracellular protein disulfide
isomerase (PDI) activity (110). The TG and G protein
signaling activities of this protein are reciprocally regulated by the binding of Ca2⫹ and GTP, respectively (38,
120, 202): calcium-activated TG2 assumes an expanded
ellipsoid structure (37, 224), while GTP binding promotes
transition to the compact, transamidase-inactive conformation (37, 162) (Fig. 1A).
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reduced hematocrit (possibly due to anemia) in the
TG2⫺/⫺ mice (41). Although no significant differences
were noted by SDS-PAGE between TG2⫺/⫺ and TG2⫹/⫹
RBC membrane fractions, high-density (“old”) but not
low-density (“young”), TG2⫺/⫺ RBCs were more resistant
to osmotic lysis than wild-type RBCs, both in the absence
of, or following, pretreatment with Ca2⫹/ionophore to
induce morphological changes (41).
As with the rat, the prime response of mouse RBCs to
Ca2⫹ influx is activation of calpain and membrane protein
degradation, with TG2-mediated cross-linking of the small
to the large subunits of ␮-calpain enhancing protease
activity (239). Following ionomycin addition to induce
cell death, cell-surface phosphatidylserine exposure was
delayed in mixed strain (SVJ129-C57BL/6) TG2⫺/⫺ relative
to wild-type RBCs, which accords with the notion that
TG2, through calpain activation, promotes cell surface
migration of phosphatidylserine (239). This notion was
strengthened by the observation that biotinylcadaverine,
a competitive inhibitor of TG2 transamidase activity, delayed phosphatidylserine exposure in wild-type, but not
TG2⫺/⫺ RBCs. To investigate whether TG2 affects RBC
survival, wild-type and TG2⫺/⫺ RBCs were stained with a
fluorescent dye, injected intraperitoneally into wild-type
mice (rather than directly reinjecting them into the circulations of the individual donor mice), and their timedependent disappearance from the circulation was followed. An unusual, early increase in life-span profile obtained for the TG2⫺/⫺ cells was interpreted to indicate a
delay, relative to wild-type cells, in TG2⫺/⫺ cell uptake
from the peritoneal cavity into the bloodstream, but otherwise, RBC survival rate was judged not to be significantly different (239).
D. Gluten Sensitivity Diseases
Gluten sensitivity diseases, which affect 1–2% of the
general population, are autoimmune disorders triggered
by dietary exposure to gluten present in wheat, barley,
and rye. Symptoms resolve with a gluten-free diet and
reoccur with resumption of gluten ingestion. Gluten proteins, which are unusually rich in proline (⬃15%) and
glutamine (⬃35%), are largely resistant to gastrointestinal
proteases due to a lack of proline- and glutamine-specific
endoprotease activity. As a result, immunotoxic peptides
accumulate and are transported by retrotranscytosis
(183) across the intestinal epithelium, where they initiate
a deleterious adaptive and innate immune response in a
proportion of genetically susceptible individuals. Common manifestations include enteropathy (celiac disease
or celiac sprue) that results from T cell-mediated flattening of the small intestinal mucosa and is characterized by
malabsorption and chronic diarrhea; dermatopathy (dermatitis herpetiformis), a blistering skin disease of the
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neither chemical nor biochemical procedures are available at present to separate the N␧-(␥-glutamyl)lysinebonded structures into their polypeptide building blocks,
indirect methods have been employed for assessing polymer composition, with good agreement between different
modes of analyses. For example, immunological approaches have utilized cross-reactive antibodies for recognizing accessible epitopes both in monomers and polymers (46), whereas the identification of tryptic fragments
from polymers has been accomplished by proteomics (L.
Lorand, personal communication). Membrane skeletal as
well as cytoplasmic proteins are incorporated into the
polymers (e.g., spectrins, ankyrin, band 4.1, hemoglobin,
among several others), and the anion transporter (band 3)
and possibly other transmembrane proteins serve to anchor the polymers firmly into the membrane.
High-molecular-weight polymers cross-linked by N␧(␥-glutamyl)lysine bonds have also been isolated from
RBCs of a Hb-Koln and a sickle cell patient (172, 173). A
causal relationship is suggested between polymer formation and the shortened life span of these cells, whereby
elevated Ca2⫹ levels in the pathological RBCs activate TG2
transamidase activity and the cells become susceptible to
survival hazards in the circulation through changes in their
physical properties (i.e., cell membrane stiffening and irreversible structural fixation of abnormal cell shape, e.g., echinocyte, sickle cell), in addition to the known translocation of
phosphatidylserine to the cell surface, which serves to attract phagocytes.
Elevated intracellular Ca2⫹ also activates membrane
proteases, which attack mainly glycophorin and the band
3 anion transporter (166). TG2-mediated cross-linking can
be uncoupled from proteolysis by differential inhibitors
(165), or by a few days of blood bank storage, which
greatly diminishes Ca2⫹-induced proteolysis without impairing TG2-catalyzed modification of membrane skeleton
(171).
In contrast to human RBCs, the prime response to
Ca2⫹ overload of rat RBCs is proteolysis of membrane
proteins (mostly band 4.1, band 3, and band 2.1 proteins)
by cytosolic proteases (mainly calpain), rather than TG2dependent cross-linking. This, incidentally, seems to explain the greater ease of fusion of rodent compared with
human RBC membranes and is attributed to the higher
ratio of protease to protease inhibitor (calpain to calpastatin) in the rodent RBC (102, 149). Given this and
other fundamental species differences (see sect. VC), it is
appropriate to question the relevance to human RBCs of
observations made with rodent RBCs.
RBCs from mixed strain (SVJ129-C57BL/6) TG2⫺/⫺
mice had no transamidating activity, as expected, and
RBC and reticulocyte counts, hemoglobin concentration,
hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin contents showed only minor abnormalities relative to wild-type mice, with a trend toward a
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
Physiol Rev • VOL
FIG. 5. Adaptive and innate immune responses to gluten in the gut.
Ingested gluten is digested by gastrointestinal proteases in the small
intestine to innocuous peptides or proteolytically resistant, glutamine
(Q)-containing immunotoxic gluten peptides. Immunogenic gluten peptides access the lamina propria by unknown mechanisms. Their Q
residues are deamidated to glutamic acid (E) by TG2, internalized by
antigen-presenting cells (APC), and presented via HLA DQ2 (or DQ8)
molecules on the surface of APC to gluten-specific, DQ2- and DQ8restricted CD4⫹ T cells in the lamina propria. The subsequent activation
and clonal expansion of the T cells results in a cell-mediated Th1
response that initiates destruction of the epithelial layer and villous
flattening as well as a humoral response that stimulates gluten-specific
and TG2-specific B cells to produce gluten- and TG2-specific antibodies.
This renders the epithelium more permeable, facilitating increased access of immunogenic gluten peptides and propagation of disease.
[Adapted from Bethune and Khosla (44).]
A microbial transglutaminase from Streptoverticillium mobaraense that is commonly used in the food
industry, for example, in seafood, meat products, noodle
pastas, dairy products, and baked goods, has recently
been shown to deamidate the same glutamine residues of
gluten peptides as TG2, thereby enhancing peptide immunogenicity and exacerbating the activation of gluten-specific T cells from celiac disease patients (74). Food indus-
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extensor surfaces of the major joints; and neuropathy
(gluten axonal neuropathy) as well as cerebellar ataxia
due to the loss of Purkinje cells. Patients develop IgA
antibodies against gluten epitopes and predominantly IgA
autoantibodies against TG2 in celiac disease (76), against
TG3 in dermatitis herpetiformis (79, 227, 242), or against
TG6 in gluten neuropathy (106). Furthermore, tissue analyses show small intestinal IgA-TG2 deposits in celiac
disease (142), dermal IgA-TG3 deposits in dermatitis herpetiformis (242), and cerebellar IgA-TG6 deposits in gluten ataxia (106).
Recent immunological and biochemical evidence indicates a central role for TG2 in the adaptive immune
response elicited in gluten sensitivity diseases (Fig. 5),
although, to date, little attention has been paid to the role
of TG3 or TG6 in the immunopathophysiology of gluteninduced dermatopathy and neuropathy. TG2 contributes
to the T cell-mediated adaptive immune response by the
selective deamidation of gluten peptides (21, 193, 230,
255, 295). These are internalized by antigen-presenting
cells and loaded onto HLA DQ2 (or DQ8) molecules on
the surface of the antigen-presenting cells. This results in
activation and clonal expansion of gluten-specific, DQ2and DQ8-restricted CD4⫹ T cells in the lamina propria,
which initiates a cell-mediated Th1 response causing
crypt cell hyperplasia and villous flattening (see Ref. 258
for review). Activated T cells also mediate the humoral
adaptive response by stimulating gluten-specific B cells to
produce gluten-specific antibodies. The transamidase activity of TG2 may also contribute to the humoral response
by forming hapten-carrier complexes in the form of covalent TG2-gluten peptide-complexes (linked via a thioester
bond to the active site Cys of TG2 or via isopeptide bonds
to particular Lys residues of the enzyme) (91) and collagen-gluten peptide-complexes (77). These complexes result in activated T cells stimulating B cells that express
TG2-specific (259) or collagen-specific (77) antibodies,
respectively. TG2 autoantibodies only partially inhibit the
transamidating activity of TG2 (78), but may play an
important role in disease initiation/progression through
molecular mimicry. Thus a subset of TG2 autoantibodies
cross-react with self-antigens such as heat shock protein
60, desmoglein 1, or Toll-like receptor 4, as well as viral
antigens (309) or deamidated gliadin-derived peptides
(144). This increases epithelial cell permeability (309) and
proliferation (33, 107), which, in turn, induces monocyte
activation (309). Cell-surface TG2 has been reported to
play a role in the innate immune response induced in
gluten sensitivity diseases by a class of immunotoxic
gluten peptides that does not stimulate gluten-specific
CD4⫹ T cells (177). However, this work needs to be
reevaluated, as the antibody used in these experiments
(monoclonal antibody 6B9) has recently been shown to
recognize CD44 and not cell-surface TG2 (263).
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E. Cataracts
Age-related cataracts are characterized by aggregation of lens proteins with subsequent lens clouding. It has
long been accepted that TG2-mediated cross-linking of
some of the ␤-crystallins (169, 195, 297), ␣B-crystallin
(104, 174), and the intermediate filament protein vimentin
(62) is likely involved. Very high (unphysiological) levels
of oxidative stress were shown to stimulate the in situ
transamidase activity of TG2 in human lens epithelial cells
(249) via transforming growth factor (TGF)-␤2 activation
of the Smad3 signaling pathway, resulting in TG2-mediated cross-linking and aggregation of lens proteins (250)
(Fig. 6). Lenses from mixed-strain (C57BL/6-SV129) TG2deficient mice cultured for 10 days with TGF-␤2 showed
no signs of cortical opacification, whereas lenses from
wild-type C57BL/6 mice opacified within 5 days of TGF-␤2
treatment and were completely opaque by day 10 (250).
Physiol Rev • VOL
Thus the transamidating activity of TG2 likely plays a
critical role in the formation of lens protein aggregates
induced by oxidative stress and may contribute to the
pathogenesis of other diseases involving TGF-␤-mediated
responses.
F. Inflammation and Tissue Remodeling/Repair
Tissue remodeling/repair is a dynamic process involving an initial inflammatory phase followed by tissue
formation/stabilization and remodeling. Many different
cell types, such as keratinocytes, platelets, macrophages,
fibroblasts, and endothelial cells, interact to facilitate remodeling (reviewed in Ref. 282). TG1 is important for
cutaneous regeneration (123). Both TG2 and FXIII-A appear to be involved in tissue injury/remodeling, although
their precise contributions to the various different stages
of injury/remodeling have not yet been fully characterized.
1. Expression of TG2 and inflammatory mediators
Increased TG2 expression and transamidation activity is a common feature of many inflammatory diseases
and events. Cytokines and growth factors secreted during
the initial phase of cell injury regulate TG2 expression
(Fig. 6). For example, TGF-␤ acts to increase TG2 in
keratinocytes (101) and on the surface of dermal fibroblasts (229) via a TGF-␤1 response element in the Tgm2
gene promoter (233). TNF-␣ enhances TG2 synthesis in
liver cells via activation of I␬B␣ phosphorylation. This
causes the dissociation of I␬B from NF␬B, allowing the
nuclear translocation of NF␬B, which then binds to the
Tgm2 promoter (153). TG2 enhances NF␬B activation
and, thus, inflammation in microglial cells, by cross-linking I␬B␣, which also results in NF␬B dissociation and
nuclear translocation (157). Increased TG2 expression,
resulting from increased binding of NF␬B to the Tgm2
promoter, enhances extracellular TG2 cross-linking activity, a response observed in experimentally induced hepatic fibrogenesis in rats (189) and in patients with hepatic disease, who have increased ECM TG2 levels (204,
222). TG2 expression is also enhanced in cartilage tissue
by interleukin (IL)-1 (129) and in liver cells by IL-6 (274).
Mallory body inclusions consisting primarily of transglutaminase cross-linked keratins 8 and 18 are characteristic
of several liver disorders, although it is not yet clear
whether these bodies protect from, or promote, injury
(310). In response to cutaneous injury, TG2 expression
and activity is increased at sites of neovascularization in
the provisional fibrin matrix, endothelial cells, skeletal
muscle cells, and macrophages infiltrating wounds in the
border zone between normal and injured tissue, and,
later, in the granulation tissue matrix where it is thought
to cross-link ECM substrates (49, 109).
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try use of microbial transglutaminases may thus be a
significant contributing factor to the development of celiac disease in susceptible individuals. The potential effect
of other forms of food processing on epitope formation is
unknown.
C57BL/6 TG2⫹/⫹ and TG2⫺/⫺ mice have been used to
verify that TG2 is an autoantigen in celiac disease patient
sera (143), and serological testing for anti-TG2 autoantibodies is now a primary tool for diagnosing individuals
with celiac disease. Attempts to establish models of gluten sensitivity in rabbits, dogs, and mice have been unsuccessful (see Ref. 44 for review). A gluten-sensitive
rhesus macaque model exhibited histological signs and
symptoms of gluten-induced enteropathy accompanied by
anti-gliadin antibody production; however, no anti-TG2
antibodies were observed and an association with MHC
class II haplotypes has not yet been confirmed (43). Coadministration of gluten and an orally active glutaminespecific endoprotease to hydrolyze glutamine-rich gluten
peptides in vivo prevented gluten-induced clinical relapse,
indicating a marked loss of T-cell reactivity towards the
shorter endoprotease-digested gluten peptides (45). Unexpectedly, however, this treatment increased the production of anti-gliadin antibodies and initiated the production of anti-TG2 antibodies. This not only suggests
more efficient penetration of the enterocyte barrier by the
shorter peptides, but more importantly, supports a noncausative role for anti-TG2 antibodies in disease progression (45). Combination enzyme therapy to digest glutamine-rich gluten peptides into even smaller (potentially
nonimmunogenic) fragments, using a glutamine-specific
endoprotease from barley as well as a bacterial prolyl
endopeptidase to detoxify prolyl-rich gluten peptides
(96), may further limit activation of the immunological
responses associated with gluten sensitivity diseases.
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
1005
Recent studies using lipopolysaccharide to induce
murine endotoxic shock demonstrated increased survival
of C57BL/6 TG2-deficient mice relative to their wild-type
counterparts (84). This was associated with decreased
NF␬B activation, decreased neutrophil recruitment into
kidneys and the peritoneum, and reduced renal and myocardial tissue damage. This phenotype indicates that TG2
promotes the pathogenesis of endotoxic shock. Further
delineation of the mechanisms involved is required.
Consistent with a stimulatory role for TG2 in inflammation is recent work using airway epithelial cells from cystic
fibrosis patients defective in the cystic fibrosis transmemPhysiol Rev • VOL
brane conductance regulator (CFTR) gene. A marked upregulation of TG2 in these cells leads to cross-linking and
subsequent proteasomal degradation of peroxisome
proliferator-activated receptor (PPAR)-␥, a nuclear hormone receptor that negatively regulates inflammatory
gene expression (Fig. 6). As a result, these patients
display an enhanced inflammatory response (178).
2. Hepatic and renal injury
TG2-deficient mice have been used in an attempt to
investigate if accumulation of TG2 during hepatic or renal
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FIG. 6. Stress, injury, and inflammatory response pathways regulating TG2 expression and/or activity. Oxidative stress triggers either an
increase in intracellular calcium levels, which stimulates TG2 transamidase activity, or TGF-␤-mediated activation of NF␬B [as a result of its release
from its I␬B␣ regulatory subunit that follows phosphorylation of I␬B␣ by I␬B kinase (IKK)], which induces TG2 expression, translocation, and
activation and results in an increased inflammatory response. Lipopolysaccharide (LPS) or cytokines also trigger activation of NF␬B, while ethanol
induces nuclear translocation of TG2. Enhanced transamidation by TG2 leads to polymerization of various substrate proteins, including crystallin,
I␬B␣, PPAR-␥, or Sp1, thereby promoting an inflammatory response or apoptosis. In cardiomyocytes overexpressing TG2, enhanced signaling
through the thromboxane A2 (TXA2) receptor (TP␣) leads to sustained activation of phospholipase A2 (PLA2) and cyclooxygenase 2 (COX-2), with
consequent hypertrophy and apoptosis. AA, arachidonic acid; iNOS, inducible isoform of nitric oxide synthase; iPs, isoprostanes; PGH2,
prostaglandin H2; PL, phospholipid; PPAR␥, peroxisome proliferator-activated receptor-␥; TGF-␤, transforming growth factor-␤; TLR4,
Toll-like receptor 4.
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IISMAA ET AL.
Physiol Rev • VOL
proximal tubular epithelial cells, have shown that TG2
contributes to renal extracellular matrix accumulation
primarily by accelerating the deposition of soluble collagens III and IV into the matrix (90). Involvement of TG2 in
interstitial renal fibrosis has also been demonstrated in
C57BL/6 TG2-deficient mice subjected to unilateral ureteral obstruction (251). Although apoptosis was similar,
fibrosis development was substantially reduced in TG2⫺/⫺
mice relative to TG2⫹/⫹ mice. This was associated with
reduced macrophage and myofibroblast infiltration and
decreased collagen I synthesis due to decreased TGF-␤
activation.
3. Phagocytosis
Macrophages that infiltrate a wound after injury contribute to the resolution of inflammation by generating
TGF-␤. In turn, activation of TGF-␤ stimulates phagocytosis of apoptotic cells and suppresses further proinflammatory mediator production (82). During monocyte differentiation into macrophages, high levels of integrinbound surface TG2 are induced (14, 196) concomitant
with a decrease in FXIIIA expression (248). This correlates with macrophage phagocytotic capacity (246, 248)
as well as macrophage adhesion and migration (14).
TG2⫺/⫺ macrophage adhesion and migration have not
been investigated directly. However, TG2⫺/⫺ mice have
been reported to exhibit a defect in macrophage clearance of necrotic or apoptotic cells. Systems that have
been studied include clearance of necrotic (204) or apoptotic (85) C57BL/6 TG2⫹/⫹ and TG2⫺/⫺ cells after hepatotoxin exposure, clearance of apoptotic cells (background
strains of TG2⫹/⫹ and TG2⫺/⫺ mice not stated) during
induced thymic involution (277), and clearance of apoptotic 94% C57BL/6 – 6% SVJ129 TG2⫹/⫹ and TG2⫺/⫺ neutrophils during goutlike peritoneal inflammation (234). This defect was associated with the development of autoimmunity in aged mice (277). However, ingestion of bacteria,
yeast, or opsonized nonapoptotic thymocytes by TG2⫺/⫺
macrophages was normal (277). This finding is in contrast
to monocytes of patients with FXIII deficiency, which
have been reported to display impaired phagocytosis of
sensitized red blood cells (Fc␥R-mediated) and of complement-coated (complement receptor-mediated) and
uncoated (lectin-like receptor-mediated) yeast particles
(243). The clinical significance of these findings, however,
is unclear, since patients with FXIII deficiency do not
have an increased susceptibility to infectious diseases
resulting from impaired phagocytic elimination of microbes (288). The impaired engulfment of apoptotic cells
(85, 234) by TG2⫺/⫺ macrophages appears to be due to a
deficiency in activation of latent TGF-␤1 (234, 277). Although the transamidase activity of TG2 has been implicated in TGF-␤ release from latent matrix storage complexes (141, 207), rescue of the defective phagocytosis by
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injury plays a protective or pathological role. Consistent
with a protective role for TG2 in liver damage, treatment
of C57BL/6 TG2-deficient mice with the hepatotoxin carbon tetrachloride resulted in an increased incidence of
death postinjury, relative to control C57BL/6 mice, an
effect associated with an increased inflammatory response and increased ECM accumulation (204). In contrast, consistent with a proapoptotic role for TG2 is the
finding that compared with their wild-type mixed-strain
(SVJ129-C57BL/6) littermates, apoptosis of hepatocytes
from TG2⫺/⫺ mice was markedly reduced following treatment of isolated hepatocytes with ethanol or treatment of
animals with a low dose (0.1 ␮g/g body wt) of the anti-Fas
antibody Jo2, which is a known, potent inducer of endothelial cell and hepatocyte apoptosis that contributes to
alcohol-induced liver damage (281). This finding contrasts
with that of an earlier study reporting increased death of
mixed-strain (SVJ129-C57BL/6) TG2-deficient mice relative to wild-type FVB mice, when treated with a high dose
(1 ␮g/g body wt) of Jo2 (240). The problem with this
earlier study is that a Jo2 dose of 1 ␮g/g body wt is
sublethal in FVB mice, whereas C57BL/6 mice are more
sensitive to Jo2, with lethality being observed at doses as
low as 0.3 ␮g/g body wt (240); thus it is not clear if the
increased sensitivity of the TG2-deficient mice was due to
the influence of their C57BL/6 genetic background or the
lack of TG2. Indeed, when using wild-type SVJ129C57BL/6 littermates from heterozygous TG2⫹/⫺ crosses,
the high dose of Jo2 used by Sarang et al. (240) caused
massive hepatic necrosis, both in TG2⫹/⫹ and TG2⫺/⫺
mice (281), indicating that the different genetic backgrounds of the wild-type and TG2-deficient mice used by
Sarang et al. (240) likely accounts for the discrepancy
between the two studies. The study of Tatsukawa et al.
(281) also highlights a role for TG2 in promoting hepatic
apoptosis caused by relatively low doses of Jo2, but not
by higher doses. The proapoptotic effect of TG2 in the
pathophysiology of liver cell death involves inactivation
of the transcription factor Sp1 by TG2-mediated crosslinking, with resultant inhibition of the expression of
genes required for cell viability (281) (Fig. 6). In a third
type of liver injury model, C57BL/6 TG2⫺/⫺ mice were
found to be highly resistant to drug-induced Mallory body
formation and associated liver hypertrophy relative to
C57BL/6 TG2⫹/⫹ mice (270). Hepatocellular damage, however, was similar between wild-type and TG2⫺/⫺ mice,
although TG2⫺/⫺ mice had marked hepatic cholestasis,
characterized by more gallstones, jaundice, and ductal
proliferation than wild-type mice (270). Thus the amelioration of Mallory body formation and injury-mediated
hypertrophy attributable to TG2 is associated not with an
improvement in liver cell damage but, rather, with increased cholestasis.
Studies using C57BL/6 TG2⫺/⫺ tubular epithelial
cells, in conjunction with transfected opossum kidney
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
4. Cell adhesion and migration
Interaction of cells with the surrounding ECM is
critical for cell adhesion and migration. The role of TG2 in
this process is being delineated primarily from cultured
cell studies. TG2 overexpression in fibroblasts increased
cell attachment (100, 298) and spreading (100). In contrast, fibroblasts deficient in TG2, that were either isolated
from mixed-strain (SVJ129-C57BL/6) mice (203) or generated by stable transfection of antisense constructs (134,
267, 298), exhibited decreased adhesion (134, 203, 298)
and spreading (134, 267). Available evidence indicates
TG2 contributes to cell adhesion in two ways (Fig. 7).
First, TG2 stabilizes ECM proteins by enhancing the initial
phase of fibronectin matrix formation (15) and by crosslinking ECM proteins (8, 93, 109). Second, cell-surface
TG2 promotes fibroblast adhesion to fibronectin (10, 16,
283, 299, 311) by interacting directly with ␤1/␤3/␤5 intePhysiol Rev • VOL
FIG. 7. Contribution of TG2 to cell adhesion. TG2-mediated cell
adhesion involves binding and cross-linking of fibronectin (shown) and
other ECM proteins, as well as promotion of cell adhesion by direct
interaction of TG2 with ␣ or ␤1/␤3/␤5 integrins, the G protein-coupled
cell-adhesion receptor GPR56, or the syndecan-4 heparan sulfate proteoglycan receptor, resulting in activation of protein kinase C-␣ (PKC-␣)
signaling.
grins (16, 97, 311), with heparan sulfate chains of the
heparan sulfate proteoglycan receptor syndecan-4 (283,
299), and with the orphan G protein-coupled cell-adhesion
receptor GPR56 (303). Enhancement of integrin- (16) or
syndecan-4-mediated (283, 299) fibroblast adhesion and
spreading on fibronectin, by cell surface TG2, is not mediated by its transamidase activity. Rather, it involves
modulation of common targets of receptor-dependent
outside-in signaling, such as PKC-␣ activation (283, 299).
During tissue injury and/or remodeling, activated matrix
metalloproteinases degrade fibronectin and other matrix
proteins to generate Arg-Gly-Asp (RGD)-containing peptides. These peptides compete with, and thus disrupt,
integrin binding to the RGD-containing domains of matrix
components, such as fibronectin, and, consequently, impair adhesion. Independent of its transamidase activity,
extracellular TG2 restores fibroblast adhesion in the presence of RGD-containing peptides (299) by direct interaction, not with integrin, but with the heparan sulfate
chains of sydnecan-4. This results in intracellular crosstalk between syndecan-4 and ␤1 integrin via syndecan4-driven activation of PKC-␣ and PKC-␣-induced ␤1integrin activation (283). Thus TG2 may have a physio-
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TG2⫺/⫺ macrophages appears not to require the transamidase activity of TG2, since it was observed even with
exogenous addition of a catalytically inactive mutant
form of TG2 (234). Furthermore, rescue of phagocytosis
appeared to be dependent on exogenous TG2 binding to
GDP or adenine nucleotide, but not to GTP. Indeed, exogenous GTP-bound TG2 inhibited phagocytosis of apoptotic cells by wild-type macrophages (234). Together,
these results indicate that a particular conformation of
TG2 is required for TGF-␤ activation during the resolution
phase of inflammation. The mechanism by which exogenous TG2 activates TGF-␤ is not yet clear and requires
further investigation.
The phagocytic capacity of neutrophils stimulated by
intraperitoneal administration of yeast extract was not
compromised in mixed strain (SVJ129-C57BL/6) TG2⫺/⫺
mice relative to those from wild-type mixed strain
(SVJ129-C57BL/6) animals (32). However, TG2⫺/⫺ neutrophils were deficient in superoxide generation (32) due to
downregulation of GP91PHOX (32), the major subunit of
the NADPH oxidase system that generates reactive oxygen species in response to invading microorganisms as
part of a phagosomal killing mechanism. TG2⫺/⫺ mice
have not yet been tested for their ability to resolve microbial infections. With the use of adhesion-dependent assays, migration of neutrophils into the peritoneum in
response to yeast extract and chemotaxis of neutrophils
towards fMLP have also been reported to be defective in
TG2⫺/⫺ mice (32). However, this study did not rule out
potential impairment of TG2⫺/⫺ neutrophil adhesion as a
contributing factor. Given that cell surface TG2 is involved in integrin-dependent fibroblast (16) and monocyte (14) adhesion and migration (see below), and that
neutrophil migration is also integrin dependent (160), the
observed neutrophil migration defect may in part be related to an adhesion defect.
1007
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IISMAA ET AL.
logical role in protecting cells from anoikis (detachmentinduced apoptosis) induced by inhibition of integrindependent adhesion following injury. Again, independent
of its transamidase activity, intracellular TG2 may also
regulate fibroblast spreading on fibronectin through
PKC-␣ activation and FAK phosphorylation (267), as well
as inhibiting smooth muscle cell motility by direct association with the cytoplasmic tail of ␣-integrin subunits
(136). Studies with TG2⫺/⫺ cells should confirm and extend these findings.
5. Arterial remodeling
Physiol Rev • VOL
Cancer progression shares many similarities with inflammatory responses (179) and tissue injury/remodeling
(244). Numerous conflicting reports implicate either TG2
up- or downregulation in this process (185). TG2 expression is often downregulated in primary tumors and during
tumor progression, whereas upregulation of TG2 is often
associated with secondary metastatic tumors and resistance to chemotherapy (reviewed in Ref. 150). Recent
studies demonstrating hypermethylation of a CpG island
that overlaps both the transcriptional and translational
start site of the TGM2 gene suggest that epigenetic gene
silencing may mediate the reduction in TG2 expression in
primary tumors (12). In N-myc-overexpressing neuroblastomas, N-myc has been shown to repress TG2 expression
by recruiting the transcription factor Sp1 and histone
deacetylase (HDAC) 1 to Sp1 binding sites in the TGM2
core promoter (163). Moreover, in contrast to the action
of FXIII-A (see sect. IID), upregulation of TG2 by N-myc
siRNA or HDAC inhibitors correlated with marked reduction in tumor growth (163). Similarly, intratumor TG2
injections inhibited CT26 colon carcinoma tumor growth
in mice (135).
The host ECM plays an important role in the regulation of tumor growth, in metastatic spread, and in tumor
angiogenesis. Thus degradation of cell-surface TG2 by
membrane type 1 matrix metalloproteinase and matrix
metalloproteinase-2 at the boundary between normal and
tumor tissue suppressed cell adhesion and migration on
fibronectin, but stimulated migration on collagen (39, 40).
Exogenous addition of TG2 increased ECM accumulation
and reduced ECM turnover, conferring resistance to ECM
degradation by matrix metalloproteinase-1 and blocking
capillary growth in in vitro angiogenesis culture studies
(135). In direct contrast to studies with FXIII-A⫺/⫺ mice
(see sect. IID), studies with mixed strain (SVJ129C57BL/6) (135) or C57BL/6 (75) TG2⫺/⫺ mice have shown
that subcutaneous implantation of B16F1 (135) or B16F10 (75) melanoma cells resulted in increased tumor size
in (75, 135), and reduced survival of, TG2⫺/⫺ mice, relative to wild-type mice (135). Hematogenous metastasis to
lung and other organs of intravenously injected tumor
cells was increased, although individual metastasis size
was smaller, in TG2⫺/⫺ compared with wild-type mice
(75). Inhibition of TG2, by treatment with TG2 inhibitors
(306, 307), antisense (108), ribozyme (108) or RNAi (13,
112, 138, 308) technologies, sensitized cancer cells to
chemotherapeutic agents by disrupting fibronectin assembly in the ECM and promoting cell death or autophagy
(306, 308). Although it is not yet clear which location or
biochemical function of TG2 is involved in these effects, it
appears that TG2 and FXIII-A have opposing roles in
cancer progression.
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Preliminary studies using TG2-deficient mice have
investigated the role of TG2 in arterial remodeling. Compared with wild-type littermates, arteries of mixed strain
(SVJ129-C57BL/6) TG2⫺/⫺ mice showed a delayed, but not
suppressed, capacity to undergo inward remodeling (that
is, a decrease in lumen diameter) in response to surgical
reduction in blood flow (31) or nitric oxide inhibitor
(N␻-nitro-L-arginine methyl ester hydrochloride, L-NAME)induced hypertension (225). Remodeling was accompanied by increased arterial expression of FXIII-A mRNA in
TG2⫺/⫺ mice and of TG2 and FXIII-A mRNA in wild-type
mice upon surgical reduction of blood flow (31), but no
differences in FXIII-A or TG2 mRNA levels were observed in wild-type or TG2⫺/⫺ mice with L-NAME-induced hypertension (225). Depletion of accumulated
adventitial monocytes/macrophages by phagocytosis of
the liposome-encapsulated toxic drug clodronate inhibited both arterial FXIIIA expression and surgically induced inward remodeling in TG2⫺/⫺ mice (31), indicating
potential compensation for TG2 in low flow artery remodeling by monocyte/macrophage-derived FXIIIA. Interestingly, L-NAME treatment resulted in stiffening of TG2⫹/⫹
but not TG2⫺/⫺ erythrocytes, indicating a role for TG2 in
erythrocyte deformability (225). The reduction in inward
remodeling observed in TG2⫺/⫺ mice in response to reduced blood flow is phenocopied in pure strain (SV129)
vimentin⫺/⫺ mice (245). Given that vimentin is a major TG
cross-linking substrate in carotid atherosclerotic plaque
(105), TG2-mediated dimerization of this integral cytoskeletal protein may regulate inward remodeling. Consistent with TG2 involvement in this process, inward remodeling in rats was inhibited by cystamine, a broadspectrum inhibitor of sulfhydryl enzymes (81). Outward
remodeling (increase in vessel size), on the other hand,
involves vimentin (245), but does not appear to involve
TG2, as this was unaffected in TG2⫺/⫺ mice (31), despite
cystamine inhibition of outward remodeling in rats (81).
Clearly, further work is required to clarify the mechanisms responsible for vascular remodeling in these various models.
G. Cancer
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
TG2 has recently been shown to interact in the ECM
with the novel G protein-coupled receptor GPR56, a suppressor of melanoma tumor growth and metastasis that is
markedly downregulated in highly metastatic cells (303)
(Fig. 7). Tumor cell growth and metastasis may thus
involve localized interactions of TG2 with GPR56, integrins, and other matrix proteins such as fibronectin. The
functional consequences on tumor growth, metastasis,
and angiogenesis of TG2 interaction with sydnecan family
members, the expression of which are often downregulated in primary tumors and upregulated in metastases
(36), have not yet been investigated.
Bones form during vertebrate development by one of
two independent, yet coupled, pathways. Those of the
skull, part of the clavicle, and the bony collars of long
bones are formed by intramembranous ossification. This
involves differentiation of mesenchymal cells into osteoblasts, which deposit an extracellular matrix that is subsequently mineralized. Bones of the axial and appendicular skeleton and most of the facial bones are formed by
endochondral ossification, whereby a hyaline cartilage
blueprint of the future skeleton is laid down in the embryo
(chondrogenesis) and then replaced by bone (osteogenesis). Some hyaline cartilage remains at the ends of the
bone in the epiphyseal growth plates to allow lengthening
of bones during childhood.
Chondrogenesis begins with the localization of undifferentiated mesenchymal cells in the site of the future
bone. Cells in the core of this localized cellular mass
differentiate into chondrocytes that express and secrete
TG2 and FXIII-A, but not TG1, TG3, or TG5 (9, 133, 211),
while a thin layer of cells that surrounds the core differentiates into perichondrial cells. The chondrocytes rapidly proliferate and secrete collagen type II and aggrecan,
resulting in the formation of cartilage.
Osteogenesis commences with cessation of chondrocyte proliferation and initiation of chondrocyte hypertrophy. Expression of both TG2 and FXIII-A is upregulated in
hypertrophic chondrocytes (9, 161, 210). These cells secrete type X collagen, a marker of chondrocyte hypertrophy, differentiate further, and deposit mineral into their
surrounding matrix. They also secrete metalloproteinases
to degrade nonmineralized matrix, and, possibly, growth
factors to induce invasion of the mineralized cartilaginous
matrix by vascular tissue, before undergoing apoptosis.
The invading vascular tissue delivers osteoclasts to the
region. Simultaneously, perichondrial cells differentiate
into osteoblasts that express and secrete both TG2 and
FXIII-A (111, 209) and form a bony collar. The FXIII-A
protein found in bone cells and bone matrix appears to be
proteolytically processed during osteoblast differentiaPhysiol Rev • VOL
tion to a 37-kDa form that retains its calcium binding
region, but not its thrombin cleavage sites (201). Osteoclasts degrade the mineralized matrix, which is then
replaced with bone matrix by osteoblasts. This osteoblast-derived bone matrix contains both collagen types I
and II and noncollagenous proteins such as fibronectin,
SIBLING (small integrin binding ligand N-linked glycoprotein) proteins, including osteopontin, bone sialoprotein, dentin matrix protein-1, and dentin phosphoprotein,
the calcium-binding cysteine-rich glycoprotein, osteonectin, and fibrillin-1 (reviewed in Ref. 208), all of which are
in vitro TG substrates. Inhibition of chondrocyte transamidase activity reduces mineralization in preosteoblasts
(18) and in cocultures of chondrocytes and preosteoblasts (209), while addition of either exogenous TG2 (132,
209) or FXIII-A increases mineralization/hypertrophy
(131). FXIII-A may have a more prominent role than TG2
in early matrix mineralization by intramolecular collagen
cross-linking, as well as cross-linking collagen and noncollagenous matrix proteins (201). Consistent with this
notion, transamidase activity of lysates prepared from
mixed strain (SVJ129-C57BL/6) chondrocytes isolated
from knees of TG2⫺/⫺ mice was reduced by only ⬃50%
compared with wild-type littermates (133), while transamidase activity in bone extracts showed no difference
between mixed strain (SVJ129-C57BL/6) wild-type and
TG2⫺/⫺ mice (201), with no substantial overexpression of
FXIII-A, or other TGs in either case. More significantly,
independently of transamidase activity, FXIII-A promotes
chondrocyte hypertrophy by interacting extracellularly
with ␣1 integrin to stimulate TG2 externalization (131)
(Fig. 8). Chondrocyte hypertrophy induced by exogenous
TG2 is independent of transamidase activity and fibronectin binding, but is ␣5/␤1 integrin dependent and is enhanced by GTP binding (132, 279). FXIII-A also appears to
be required intracellularly as exogenously added FXIII-A
did not induce chondrocyte hypertrophy in mixed-strain
(129Ola-CBACa) FXIII-A⫺/⫺ chondrocytes (131). Induction of hypertrophy by FXIII-A and TG2 is associated with
FAK and p38MAPK phosphorylation (131, 279). These
studies thus indicate important temporal signaling roles
for FXIII-A and TG2. This involves extracellular fibronectin-independent interactions between FXIII-A and ␣1␤1
integrin, followed by interactions between GTP-bound
TG2 and ␣5/␤1 integrin. These interactions mediate the
induction of chondrocyte hypertrophy and consequent
mineralization. Despite this evidence for the involvement
of FXIII-A and TG2 in bone development, no gross skeletal abnormalities are found in either TG2 (73, 203) or
FXIII-A (156) knockout mouse models. Thus, although the
functions of TG2 and FXIII-A may be coordinated in developing bone, with both enzymes potentially promoting
cell adhesion, matrix assembly and mineralization and
matrix-mediated cell differentiation, neither of the indi-
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H. TG2, FXIII-A, Bone, and Osteoarthritis
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vidual TGs alone is critical for bone development and one
can perhaps compensate for loss of the other.
Osteoarthritis, a condition that affects more than 20
million people in the United States alone, is associated
with regions of articular chondrocyte hypertrophy, formation of osteophytes (bony outgrowths), and degeneration
of cartilage. Articular cartilage (hyaline cartilage without
a perichondrium), which cushions the ends of bones in
joints by elaborating synovial fluid in response to loading,
normally contains resting chondrocytes that do not
differentiate or mineralize their surrounding matrix. A
number of proinflammatory factors known to stimulate
chondrocyte hypertrophy are upregulated in osteoarthritic cartilage, such as IL-1␤ (24) and the CXC chemokine subfamily members IL-8 (CXCL8) and growthPhysiol Rev • VOL
I. Cardiovascular Disease
Various parameters of cardiac function (heart rate,
systolic and diastolic blood pressure, maximum rates of
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FIG. 8. Contribution of TG2 to osteogenesis and osteoarthritis.
Chondrocyte hypertrophy is induced temporally by FXIII-A-dependent,
followed by TG2-dependent, integrin interactions resulting in MAPK
activation. This progresses to osteoarthritis during low-grade, chronic
inflammation through interleukin 1␤ (IL-1␤)-stimulated secretion of
S100A11 and expression of the receptor for advanced glycation end
products (RAGE), TG2-mediated formation of the dimeric S100A11
RAGE ligand, and subsequent activation and propagation of MAPK and
NF␬B signaling.
related oncogene ␣ (GRO␣; CXCL1) (48). IL-8 signals
through CXCR1 and CXCR2, whereas GRO␣ activates
CXCR2, but not CXCR1 (213). Both IL-8- and GRO␣-induced hypertrophy of wild-type murine chondrocytes is
associated with increased transamidase activity (186).
Unlike lysates prepared from murine knee chondrocytes isolated from mixed-strain (SVJ129-C57BL/6)
wild-type mice, those from TG2⫺/⫺ littermates showed
no increase in transamidase catalytic activity or matrix
calcification in response to stimulation with IL-1␤, GRO␣,
or the all-trans form of retionoic acid (ATRA). They also
failed to exhibit features characteristic of chondrocyte
hypertrophy, such as collagen X secretion (133, 186) and
expression of the transcription core binding factor ␣1
Cbfa1 (133). In contrast, stimulation of both wild-type
mixed-strain (SVJ129-C57BL/6) and TG2⫺/⫺ littermate
knee chondrocytes with C-type natriuretic peptide (CNP),
an essential factor in endochondral development, resulted
in comparable Cbfa1 expression and chondrocyte hypertrophy without associated mineralization or modulation
of transamidase activity (133). These studies thus support
a direct contribution of TG2 to IL-1␤-, GRO␣-, and ATRAinduced transamidase activity and mineralization and
demonstrate that there are distinct TG2-dependent (IL1␤-, GRO␣-, or ATRA-induced) and TG2-independent
(CNP-induced) pathways of chondrocyte hypertrophy.
The transamidase activity of TG2 has recently been
implicated in promoting osteoarthritis progression. Studies using murine femoral head articular cartilage explants
and knee chondrocytes from C57BL/6 TG2⫺/⫺ mice have
shown that the transamidase activity of TG2 is required to
convert S100A11 (a calcium-binding, EF-hand S100/calgranulin protein secreted in response to IL-1␤ during
low-grade chronic inflammation) into a covalent homodimer (Fig. 8). This accelerates chondrocyte hypertrophy and matrix catabolism via receptor for advanced
glycation end products (RAGE) signaling (58). In a surgically induced knee joint instability model of osteoarthritis, mixed strain (SVJ129-C57BL/6) TG2⫺/⫺ mice
had reduced cartilage destruction and increased osteophyte formation relative to wild-type littermates (214).
This phenotype was associated with increased expression of TGF-␤1, which promotes osteophyte formation
(30), in the osteoarthritic tissues of the TG2⫺/⫺ mice
compared with TG2⫹/⫹ mice (214). Together, these studies point to a role for TG2 in modulating cartilage repair
and stability in response to certain pathological stressors
and identify TG2 as a potential target for therapeutic
intervention in osteoarthritis.
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
Physiol Rev • VOL
biosynthesis of the prostanoid thromboxane (TxA2), and
enhanced signaling from its G protein-coupled receptor,
TP␣ (312) (Fig. 6). This response leads to ERK1/2 activation, which results in a feed-forward loop that accounts
for the hypertrophy, as well as for sustained activation of
phospholipase A2 and induction of the prostanoid biosynthetic enzyme COX-2 and, as a consequence of the latter,
enhanced TxA2 production (119, 312) Coincident increased oxidant stress leads to oxidative modification of
arachidonic acid and formation of free radical-catalyzed
products called isoprostanes (iPs). Formed initially in situ
in the phospholipid domain of cell membranes, they are
then cleaved by phospholipases, circulate in esterified
and unesterified forms, and importantly, act as incidental
ligands for prostanoid receptors (152). Oxidant stress
thus contributes to the hypertrophy phenotype via TP
stimulation (119, 312). Apoptosis may be a direct result of
enhanced TP␣ signaling (95) or may be secondary to
TP-mediated vasoconstriction causing myocardial ischemia. Although intracellular TG2 levels were elevated in
the cardiac TG2-overexpressors relative to control mice,
intracellular transamidase activity was not measured
in vivo or in intact cardiomyocytes. It is thus not clear if
the transamidase activity of TG2 contributes to the regulation of COX-2 expression. Nevertheless, these studies
provide compelling evidence for a potential link between
TG2 and prostanoids in cardiac dysfunction due to hypertrophy disorders in humans.
In atherosclerosis, fatty material is deposited in arterial walls, and subsequent migration of inflammatory cells
(macrophages and T lymphocytes) and vascular smooth
muscle cells into the lesion forms a plaque that results in
a narrowing of the lumen that may eventually impair
blood flow, either directly or as a result of plaque rupture,
which leads to the rapid formation of an occlusive thrombus. TG2 expression in intimal and medial smooth muscle
cells, and in the extracellular matrix, increases concomitantly with the progression of atherosclerosis (25, 273),
with leukocytes being the major source of TG2 in atherosclerotic lesions (47). Apoptosis is observed in developing
plaques, with endothelial cell and macrophage apoptosis
increasing early in atherogenesis, and vascular smooth
muscle cell and macrophage apoptosis contributing to
plaque rupture (269). Recent work indicates macrophage-expressed TG2 limits expansion of atherosclerotic
plaques (47). Thus, following a high-fat diet to induce
atherosclerosis in irradiated C57BL/6 low-density lipoprotein receptor knockout (LDLR⫺/⫺) mice that had been
transplanted with mixed-strain (94% C57BL/6 – 6% SVJ129)
wild-type or TG2⫺/⫺ bone marrow, significantly larger
aortic valve atherosclerotic lesions were observed in
those animals that received the TG2⫺/⫺ marrow (47).
Lesions in recipients of TG2⫺/⫺ bone marrow appeared to
have more expanded necrotic cores, indicative of plaques
that are vulnerable to rupture, with macrophages local-
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contractility and relaxation) were measured in mixedstrain (SVJ129-C57BL/6) TG2⫺/⫺ mice at rest and shown
not to be different from those of wild-type littermates
(203). In contrast, a recent study reported that TG2⫺/⫺
mice (the background strain was not indicated) had reduced heart rate, coronary flow, aortic flow, and aortic
pressure as well as reduced myocardial ATP levels, compared with C57BL/6 wild-type controls (241, 276). Moreover, in response to an ischemia/reperfusion challenge,
infarct size was reported to be increased in TG2⫺/⫺
hearts, as was the incidence of reperfusion-induced ventricular fibrillation, and ATP levels were even further
reduced (276). Nevertheless, given that the preischemic
coronary flow was already substantially reduced in these
TG2⫺/⫺ hearts, the validity of determining energy substrates, in this context, is questionable. Surprisingly, however, two earlier studies from the same group reported no
significant difference in ATP levels in heart, liver, skeletal
muscle (180), or brain (34) in the TG2⫺/⫺ mice at rest.
Only one of these studies (34) specified the background
strain of the TG2⫺/⫺ mice used, which was C57BL/6 (i.e.,
mixed SVJ129-C57BL/6 backcrossed for 10 generations to
C57BL/6). Upon exercise (180) or in response to a toxin
challenge (34), ATP content in brain and skeletal and
cardiac muscle appeared to be depleted due to reduced
activity of mitochondrial complex I, and increased activity of mitochondrial complex II. Given the absence of
precise animal husbandry details, the discrepancies in
cardiac function and ATP levels of TG2⫺/⫺ mice at rest
(Ref. 276 versus Refs. 34, 180, 203) may merely reflect
different husbandry practices and/or the use of nonlittermate controls.
Cardiac hypertrophy is an adaptive response to increased work load induced by pressure- or volume-overload and, in response to chronic overload, cardiac function deteriorates, resulting in decompensated heart failure. Steady-state TG2 mRNA levels are increased in both
volume- and pressure-overload-induced hypertrophied rat
ventricles and are further increased during the transition
to heart failure (125). Increased TG2 expression has also
been documented in failing hearts from patients with
dilated but not ischemic cardiomyopathy, although both
the GTP-binding and transamidase activities of TG2 were
decreased in both (115). The hypertrophic effect of transgenic cardiac-specific TG2 overexpression has been investigated in the mouse by two independent groups (256,
312). Animals between 3 and 4 mo of age developed a
unique type of cardiac hypertrophy with a mild elevation
in some markers of hypertrophy (␣-myosin heavy chain
and ␣-skeletal actin) but not others (atrial naturietic factor) (256). Older animals (7–10 mo old) developed cardiac
decompensation characterized by cardiomyocyte apoptosis and fibrosis, with an increase in mortality evident by
15 mo (312). The primary and initiating event underlying
the cardiac failure observed in these mice was increased
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J. Neurodegenerative Disorders
Increased levels and activity of TG2 have been observed in many neurodegenerative diseases. Studies with
TG2⫺/⫺ mice have demonstrated that TG2 accounts for at
least two-thirds of the transamidase activity in mouse
forebrain lysates, is localized predominantly in neurons
(27, 151), and contributes to the pathogenesis of Huntington’s disease. Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by extensive neuronal cell apoptosis in the striatum and cerebral
cortex, leading to progressive motor dysfunction and psychiatric disturbances with gradual dementia. It is caused
by an expansion of ⬃40 or more CAG repeats in the gene
encoding the cytosolic protein, huntingtin (htt) (176). Increased length of CAG repeats correlates with earlier age
of disease onset (176). Since CAG encodes glutamine (Q),
CAG repeats result in mutant htt proteins with long NH2Physiol Rev • VOL
terminal polyQ tracts (176). Given that Q residues are
potential substrates for TG-mediated cross-linking, it was
initially postulated that TGs contribute to disease pathogenesis by catalyzing the covalent formation of large Q-Q
linked insoluble htt aggregates. However, it is now clear
that such aggregates are due to noncovalent hydrogen
bonding interactions or polar zippers between adjacent Q
residues (176). Similarly, although insoluble htt aggregates were originally proposed to cause neurotoxicity,
recent evidence suggests that it is the soluble forms of
mutant htt that are neurotoxic (reviewed in Refs. 188,
235). TG2 ablation in R6/1 (181) and R6/2 (29) mouse
models of Huntington’s disease is associated with increased life span and improved motor function. Nonetheless, in keeping with a role of the soluble rather than
aggregated forms of htt being neurotoxic, TG2 ablation in
the R6/1 and R6/2 animals resulted in increased aggregate
formation (29, 181). Thus TG2 apparently inhibits aggregate formation, an effect that in vitro appears to result
from TG2-mediated cross-links increasing the solubility of
polyQ-expanded htt aggregates (155). It is possible, therefore, that TG2 contributes to the pathogenesis of Huntington’s disease, not by promoting htt aggregate formation,
but somewhat counterintuitively by increasing the formation of soluble high-molecular-weight htt complexes.
The well-established therapeutic benefit of treating
transgenic mouse models of Huntington’s disease with
cystamine, a broad-spectrum inhibitor of sulfhydryl enzymes (reviewed in Ref. 235), has been shown to be
independent of its ability to inhibit TG2 activity, since the
delayed onset of motor abnormalities and extended life
span following cystamine administration was similar in
R6/2 TG2⫹/⫹ and R6/2 TG2⫺/⫺ mice (28).
Alzheimer’s disease, characterized by progressive
neurodegeneration and a decline of cognitive function, is
associated with the accumulation of fibrillar ␤ amyloid
(A␤) in extracellular plaques. Disease severity correlates
with impaired G␣q/11-coupling of the M1 muscarinic receptor (290). Recent studies, using TG2-encoding lentivirus injection in a transgenic mouse model of Alzheimer’s
disease (APPSw), indicate this is due to the formation of
angiotensin II type 2 (AT2) receptor oligomers in the brain
that sequester G␣q/11 (1). AT2 oligomers are triggered
dose-dependently by aggregated A␤ in a two-step process
involving oxidative cross-linking to form dissociable AT2
receptor dimers that do not sequester G␣q/11 (1), followed
by TG2-dependent cross-linking of residues in the receptor COOH terminus to form nondissociable AT2 receptor
oligomers (2).
Excitotoxic neuronal cell death, caused by calcium
overload following overactivation of ionotropic glutamate
receptors, is an important component of acute neuronal
injury and chronic neurodegenerative disorders (23).
Transgenic mice that overexpress human TG2 primarily
in neurons, which resulted in ⬃70-fold increase in in vitro
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ized deeper in the intima than in those that received the
wild-type bone marrow. The function of TG2 as an integrin-associated adhesion receptor involved in monocyte
migration (14) may account for the lack of macrophages
at or near the endothelium of knockout bone marrow
recipients, while decreased extracellular matrix crosslinks (47) and a decrease in the efficiency of apoptotic cell
clearance (47, 277) by TG2⫺/⫺ macrophages may contribute to atherosclerotic expansion in the same animals (47).
In addition, decreased macrophage activation of TGF-␤
(277), which is thought to stabilize plaques by stimulation
of collagen synthesis (47), may promote plaque instability
in knockout recipients. Interestingly, irradiated LDLR
knockout mice transplanted with TG2⫺/⫺ bone marrow
had significantly lower triglyceride levels after 4 and 8 wk
on a high-fat diet (47). However, the cause and potential
implications of this finding remain unclear.
Atherosclerotic lesions calcify nonlinearly over time
as a result of osteogenic and chondrogenic differentiation
of vascular smooth muscle cells in a process akin to bone
formation (see Ref. 4 for review). Although minor differences were observed between freshly isolated 99.6%
C57BL/6 – 0.4% SVJ129 TG2⫹/⫹ and TG2⫺/⫺ mouse aortic
smooth muscle cells and aortas, stimulation of smooth
muscle cells (by an inorganic phosphate donor or by bone
morphogenetic protein-2) to drive intra-arterial chondroosseous differentiation and calcification, failed to induce
either differentiation or calcification of TG2⫺/⫺ smooth
muscle cells (130). This indicates a central role for TG2 in
these processes. Exogenous addition of TG2 to mouse
vascular smooth muscle cells has been shown to enhance
calcification via binding to low-density lipoprotein receptor-related protein 5 (LRP5) and subsequent activation of
␤-catenin signaling (86). TG2 released during artery wall
repair may thus promote calcification.
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
K. Diabetes
Maturity-onset diabetes of the young (MODY) is a
heritable variant of type 2 or non-insulin-dependent diabetes mellitus (NIDDM) that occurs in nonobese individuals and presents in adolescence or when subjects are in
their early 20s. Mutations in several genes (e.g., glucokinase, transcription factors) that impair insulin secretion
have been implicated in its pathogenesis (83). Another
potential candidate gene for MODY is TGM2, with heterozygous missense mutations that impair transamidase
activity (M330R, I331N, or N333S) having been identified
in one or more affected individuals of three different
families (42, 226). TG2 is the predominant TG expressed
in pancreatic islets (226), and its transamidase activity
has been suggested to modulate the exocytosis of glucose-stimulated insulin secretion that accompanies calcium influx into pancreatic ␤-cells (51). Consistent with
an involvement in insulin release but not synthesis, pancreatic islets from mixed strain (SVJ129-C57BL/6) TG2⫺/⫺
mice were unchanged from wild-type islets with respect
to total insulin content, islet size, or morphology (42).
However, less insulin was secreted relative to wild-type
Physiol Rev • VOL
islets in response to a high glucose challenge. This was
reflected in lower blood insulin and higher blood glucose
levels in TG2⫺/⫺ mice following intraperitoneal glucose
loading (42). Paradoxically, TG2⫺/⫺ mice showed a hypoglycemic response to exogenous insulin, indicating increased insulin sensitivity (42), a phenomenon that has
not been reported in MODY patients. The defect in
TG2⫺/⫺ glucose-stimulated insulin release has been attributed to mitochondrial TG2 functioning as a protein disulfide isomerase to reduce mitochondrial respiratory chain
activity and, consequently, ATP production, thereby resulting in a dramatic decrease in the general motility of
TG2⫺/⫺ mice (180). However, such a pathogenetic mechanism is not generally associated with MODY. Moreover,
a detailed study failed to find TG2 in mitochondria (151),
and reduced motility due to low ATP levels (the basis for
postulating the above pathogenetic mechanism) is not
observed in all TG2⫺/⫺ colonies (as discussed in sect. I
above). Thus the precise role, if any, of TG2 and TGM2
mutations in MODY pathogenesis remains unclear.
V. PROTEIN 4.2
A. General Overview and Protein Expression
Protein 4.2 (also known as band 4.2 or pallidin) is the
only catalytically inactive member of the TG superfamily.
Encoded by the EPB4.2 gene on human chromosome
15q15.2 (Fig. 1B), protein 4.2 is a 72-kDa peripheral membrane protein that is restricted to cells of the erythroid
lineage (313) and accounts for ⬃5% of the total RBC
membrane protein (264). Protein 4.2 is myristylated (232)
and palmitoylated (71). It binds ankyrin (145) as well as
the cytoplasmic domain of anion exchanger 1 (AE1, also
known as band 3) (146), both of which, in turn, link the
erythrocyte membrane to the underlying cytoskeleton. It
thereby contributes to membrane shape and stability. Protein 4.2 also associates with the Rhesus (Rh) protein
complex (Rh-associated glycoprotein, Rh polypeptides,
glycophorin B, CD47, LW) in RBC membranes (194).
In contrast to many other TGs, protein 4.2 binds ATP
but not GTP (26), although the significance of this is as yet
unknown.
B. Protein 4.2 Mouse Model
Mixed strain (SVJ129-C57BL/6) protein 4.2-deficient
mice (219) were developed by replacement of exons 4 –7
and part of exon 8 (which encode most of the catalytic
core domain) with a neomycin resistance gene (Fig. 1B).
Homozygous 4.2⫺/⫺ mice were phenotypically indistinguishable from wild-type mice and were born at the expected Mendelian frequency. RBCs from 4.2⫺/⫺ mice were
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cross-linking activity, displayed significantly more hippocampal neuron apoptosis than control mice following
kainic acid-induced overstimulation of glutamate receptors (291). Thus TG2 may contribute to neurodegenerative diseases by facilitating excitotoxic-induced neuronal
cell death.
Although elevated TG2 expression and activity have
also been linked to the pathogenesis of Parkinson’s disease, amyotrophic lateral sclerosis, and other neurodegenerative disorders (reviewed in Ref. 235), mechanistic
studies in TG2-modified animals, aimed at evaluating the
role of TG2 in these diseases, have not yet been undertaken. Recent studies suggest that TG2-mediated intraand intermolecular cross-linked ␣-synuclein is unable to
form the cytotoxic, structured fibrillar aggregates responsible for neural membrane disruption in Parkinson’s disease (247). TG2-mediated cross-linking may, thus, prevent
progression of Parkinson’s disease. A short isoform of
TG2 that was originally identified in Alzheimer’s disease
brains (61) and is unable to bind GTP, appears to be
cytotoxic to NIH-3T3 and SKBR3 breast cancer cells following transamidation activity-independent self-aggregation (20). Double mutants of TG2, that are both GTP
binding and transamidation defective, were also proapoptotic in NIH-3T3 cells, highlighting the importance of GTP
binding for the antiapoptotic function of TG2 (72). It
remains to be determined if the proapoptotic function of
the short TG2 isoform plays a role in TG2-associated
neuronal cell death in neurodegenerative disease progression.
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IISMAA ET AL.
smaller than wild-type RBCs due to membrane loss, were
dehydrated due to altered cation concentrations, had reduced levels of band 3, and were mildly spherocytic instead of biconcave due to loss of lipid anchoring and
increased fragility of the RBC membrane.
C. Hereditary Spherocytosis
VI. CONCLUSIONS AND FUTURE DIRECTIONS
It is clear from TG-deficient patients and genetically
engineered TG-deficient mouse models that four of the
nine human TGs, i.e., FXIII-A, skin and hair TGs 1 and 5,
and protein 4.2, have distinct biological roles: the clotting
disorders in FXIII-deficient patients that are phenocopied
in FXIII-A-deficient mice demonstrate the integral extracellular cross-linking role unique to pFXIIIa in blood coagulation; the intracellular cross-linking roles unique to
TG1 or TG5 in skin barrier formation are evident from
TG1- or TG5-deficient patients and from TG1-deficient
mice; and despite species differences between mouse and
human RBCs, the noncatalytic, intracellular structural
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Hereditary spherocytosis, the most common inherited disorder of the RBC membrane, is characterized by
ion transport abnormalities accompanied by osmotic
changes that lead to hemolytic anemia, jaundice, and
enlargement of the spleen. Numerous mutations underlie
hereditary spherocytosis, including those in genes encoding the proteins, spectrin, ankyrin, band 3, and protein 4.2,
which connect the membrane skeleton to the lipid bilayer.
However, mutations in the gene encoding protein 4.2 are
rare; for a comprehensive list of EPB4.2 mutations, see
Online Mendelian Inheritance in Man. In humans, expression of band 4.2 is reduced as a result of band 3 mutation
(127, 236) and is totally absent in band 3⫺/⫺ mice (220).
Taken together with data from 4.2⫺/⫺ mice, which display
a reciprocal reduction in band 3 anion exchanger activity
due to reduced levels of band 3 (219), this indicates that
binding of protein 4.2 to band 3 enhances band 3-mediated anion transport by enhancing membrane incorporation of band 3, a finding that has been confirmed in
Xenopus oocyte expression studies using wild-type protein 4.2 (289).
Human erythrocyte membranes completely lacking
protein 4.2 are severely depleted in the CD47 component
of the Rh protein complex (50), whereas RBC membranes
from 4.2⫺/⫺ mice displayed normal CD47 expression
(194). Thus, although human protein 4.2 influences CD47
levels and is critical for linkage of CD47 to the membrane
skeleton (63), this function does not appear to be conserved across species. This again questions the relevance
to human RBCs of studies done in the mouse (see also
sect. IVC).
role of protein 4.2 in ion transport across the RBC membrane is apparent from protein 4.2-deficient mice and
various human mutations that reduce intracellular protein
4.2 levels. Mice deficient in TG3 appear to have altered
hair ultrastructure, although detailed phenotypic analysis
of this model has yet to be published. Mice deficient in
TG4, TG6, or TG7 have not yet been reported, nor have
mutations in these proteins been linked to human disease.
Mutations in human TG2 have been linked to diabetes; however, available evidence from biochemical studies and TG2-deficient mouse models indicates a pleiotropic role for TG2 in pathophysiological conditions, or in
amplifying or moderating pathophysiological influences.
TG2 has been shown to be involved in cataract development, gluten sensitivity diseases, neurodegeneration, and
tissue remodeling associated with cancer, wound repair,
and bone development. The transamidase activity of TG2
plays a critical role in the formation of lens protein aggregates induced by oxidative stress. The extracellular
transamidase and deamidase activities of TG2 are central
to the adaptive immune response that is elicited in gluten
sensitivity diseases. Whereas TG2-mediated cross-linking
of amyloid-forming proteins may prevent Parkinson’s disease progression, TG2 may contribute to the pathogenesis of Alzheimer’s disease and Huntington’s disease by
mediating the formation of AT2 receptor oligomers and
the formation of soluble high-molecular-weight htt
complexes, respectively. The role of the short, proapoptotic, neural TG2 isoform in neurodegenerative
disease progression remains to be investigated. The
transamidase activity of TG2 contributes to extracellular
matrix mineralization during bone development, to the
excessive matrix mineralization characteristic of bone
pathologies, such as osteoarthritis, and to stabilization of
host matrix proteins that may retard tumor progression.
Extracellularly, and independently of its cross-linking activity, TG2 promotes cell adhesion during tissue remodeling by stabilizing the ECM and by interacting with cellsurface adhesion receptors such as ␤1/␤3/␤5 integrins
and the heparan sulfate proteoglycan receptor syndecan-4. More specifically, and perhaps more relevant to
wound healing or cancers than to bone development,
extracellular TG2 may function in syndecan adhesionmediated signaling cascades that alter or amplify integrinmediated signaling pathways. TG2 also functions intracellularly, to regulate cell spreading and motility independent of its cross-linking activity and, upon overexpression
in cardiac cells, to enhance signaling through the prostanoid biosynthetic pathway leading to cardiac hypertrophy
and contractile dysfunction. However, it is not yet known
if it is the transamidase activity of TG2 or its other functions that contribute to cardiac hypertrophy. Intracellularly, as a transamidase, TG2 enhances inflammation
through cytosolic cross-linking of I␬B␣, which enhances
nuclear translocation and activation of the transcription
TRANSGLUTAMINASES IN PHYSIOLOGY AND DISEASE
Physiol Rev • VOL
about which little is currently known, is how TG2 is
secreted from the cell. Further dissection of the overlapping or opposing roles of TG2 and FXIII-A would benefit
from the use of tissue-specific, temporal-specific, or double-knockout mouse models. However, such studies must
ensure the use of appropriate littermate controls to avoid
potentially confounding background genetic variations.
Finally, a major challenge will be the development, and
temporal analysis in animal models, of specific pharmacological inhibitors of transamidase activity for efficacious treatment of cataracts, gluten sensitivity and neurodegenerative diseases, osteoarthritis, hypertension, and
cancer.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: S. E.
Iismaa or R. M. Graham, Molecular Cardiology and Biophysics
Division, Victor Chang Cardiac Research Institute, 405 Liverpool St., Darlinghurst, Sydney, NSW 2010, Australia (e-mails:
[email protected] or [email protected]).
GRANTS
This review was made possible through research funding
from National Health and Medical Research Council Grants
459406, 526622, and 568753 and from Australian Research Council Grant DP0665422.
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required for the expression of cell viability genes. TG2 has
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