The Mechanism of Tissue-Restricted Antigen
Gene Expression by AIRE
Kristina Zumer, Kalle Saksela and B. Matija Peterlin
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References
J Immunol 2013; 190:2479-2482; ;
doi: 10.4049/jimmunol.1203210
http://www.jimmunol.org/content/190/6/2479
The Mechanism of Tissue-Restricted Antigen Gene
Expression by AIRE
Kristina Žumer,* Kalle Saksela,* and B. Matija Peterlin*,†
The autoimmune regulator is a critical transcription
factor for generating central tolerance in the thymus.
Recent studies have revealed how the autoimmune regulator targets many otherwise tissue-restricted Ag genes
to enable negative selection of autoreactive T cells. The
Journal of Immunology, 2013, 190: 2479–2482.
*Department of Virology, Haartman Institute, Helsinki University Central Hospital,
University of Helsinki, FIN-00014 Helsinki, Finland; and †Department of Medicine,
The Rosalind Russell Medical Research Center, University of California at San Francisco, San Francisco, CA 94143
Received for publication November 21, 2012. Accepted for publication January 8, 2013.
Address correspondence and reprint requests to Dr. B. Matija Peterlin, University of
California at San Francisco, 533 Parnassus Avenue, Box 0703, Room U-432, San
Francisco, CA 94143-0703. E-mail address: [email protected]
Abbreviations used in this article: AIRE, autoimmune regulator; APECED, autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy; CTD, C-terminal domain; DNAwww.jimmunol.org/cgi/doi/10.4049/jimmunol.1203210
PK, DNA-dependent protein kinase; DSIF, 6-dichloro-1-a-D-ribofuranosylbenzimidazole
sensitivity inducing factor; H3K4, histone H3 unmodified at Lys4; HSR, homogeneously
staining region; NELF, negative elongation factor; PHD, plant homology domain; PTEFb, positive transcription elongation factor b; RNAPII, RNA polymerase II; SAND,
Sp100, AIRE-1, NucP41/75, and DEAF-1; TAD, transcriptional activation domain;
TRA, tissue-restricted Ag.
Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00
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T
he autoimmune regulator (AIRE ) gene was identified
by positional cloning of the genetic locus linked to a
rare autoimmune disease, autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (1, 2).
The encoded AIRE protein is expressed primarily in medullary thymic epithelial cells (mTECs) (3). AIRE is also expressed in peripheral lymphoid tissues (4), where its contribution to tolerance remains to be investigated. The mouse
model of the human APECED disease, the Aire2/2 mouse,
was instrumental in identifying the cellular role of AIRE,
which is to regulate promiscuous expression of tissue-restricted
Ag (TRA) genes in mTECs (5). The key finding was that
mTECs from Aire2/2 versus wild-type mice expressed fewer
TRAs. Although this promiscuous gene expression in mTECs
had been recognized previously (6), the underlying mechanism remained elusive. To date, AIRE is the only identified
transcription factor that regulates this process. Among others,
AIRE activates insulin, interphotoreceptor retinoid-binding
protein A, and mucin 6 genes, all of which had been linked
to autoimmunity in humans or AIRE-deficient mice (7, 8).
Expressed TRAs are then processed and presented on the
surface of mTECs or taken up by dendritic cells (9, 10). Exposure of maturing T cells to these Ags is critical for negative
selection of T cells in the thymus (11, 12). In the absence of
AIRE, autoreactive T cells mature and escape into the periphery, which can lead to autoimmunity (7, 8, 13).
Transcription of protein-coding genes occurs in several
phases, all of which are regulated (14). First, transcription
factors and RNA polymerase II (RNAPII) are recruited to
promoters. Although RNAPII initiates transcription, it then
pauses because of the action of negative elongation factor
(NELF) and 6-dichloro-1-a-D-ribofuranosylbenzimidazole sen-
sitivity inducing factor (DSIF). The release of RNAPII to
elongation is mediated by the positive transcription elongation factor b (P-TEFb), composed of a regulatory cyclin subunit (CycT1 or CycT2) and the cyclin-dependent kinase 9
(15). P-TEFb phosphorylates subunits of DSIF and NELF as
well as serine residues at position 2 (Ser2) in the C-terminal
domain (CTD) repeats of the largest RNAPII subunit (RPB1)
(16). DSIF is thus changed to an elongation factor, NELF is
released from the nascent RNA, and the phosphorylated
RNAPII can now elongate (16). The CTD of human RNAPII
contains 52 heptapeptide repeats (YSPTSPS). The serines,
threonines, and tyrosines in these repeats are phosphorylated
by P-TEFb and other kinases in distinct phases of transcription, giving rise to diverse set of instructions, which are
known as the CTD code (17). The phosphorylated elongating
RNAPII directs cotranscriptional processing, that is, splicing
and polyadenylation of genes (18). Transcription elongation
proceeds until termination, upon which RNAPII becomes
dephosphorylated, and the cycle begins anew. Recent genomewide analyses revealed an unexpectedly high abundance of
paused RNAPII at most promoters, including those of inactive genes (19–22).
AIRE is a transcription factor that assembles into oligomers
and forms punctate structures that colocalize with CREBbinding protein, P-TEFb, and small nuclear ribonucleoproteins in the nucleus (23–25). The estimated number of AIREregulated genes ranges from several hundred to thousands.
They have diverse promoters and are regulated by distinct
transcription factors in their corresponding tissues. These
findings raise the conundrum of how AIRE can regulate such
a large repertoire of divergent genes. Recent work from others
and us has addressed this question and revealed the mechanisms of action of this enigmatic protein (26–31).
The AIRE protein has a predicted molecular mass of 58
kDa (Fig. 1A) (3). It forms large oligomers, which are detected
in a .670-kDa fraction by gel filtration (32). The N terminus
of AIRE contains the homogeneously staining region (HSR)
and the Sp100, AIRE-1, NucP41/75, and DEAF-1 (SAND)
domain (Fig. 1A). Mutations in HSR from APECED patients
2480
BRIEF REVIEWS: MECHANISM OF AIRE FUNCTION
disrupt multimerization, which is essential for AIRE function
(32, 33). The AIRE SAND domain is also involved in this
oligomer formation. It lacks the canonical KDWK motif,
which is required for DNA binding of other SAND domains
(34). Although DNA binding of the AIRE SAND domain
had been reported in vitro (35, 36), it appears to be nonspecific (37) and may be irrelevant for its recruitment to target
genes in vivo. Indeed, we found that mutating KNKA residues in the AIRE SAND domain, which correspond to the
KDWK motif in other members of this family, had no effect
on AIRE-induced expression of a plasmid reporter gene (26).
In some APECED patients an autosomal-dominant G228W
mutation was found in the SAND domain (Fig. 1A), which
causes the wild-type AIRE protein to coaccumulate in larger
structures that do not colocalize with sites of active transcription (25). Thus, dominant-negative effects of this
G228W mutation could be due to an increased affinity for the
wild-type AIRE protein. The N terminus of AIRE is required
for nuclear localization (38). The nuclear localization signal
was mapped to basic residues from positions 131 to 133 (Fig.
1A) (39).
AIRE also contains two plant homeodomains, plant homology domain (PHD)1 and PHD2 (Fig. 1A). PHDs are zinc
fingers closely related to RING domains, which are common
in proteins involved in ubiquitylation (40). PHDs are protein–protein interaction modules, which can mediate binding
to nucleosomes (41, 42). Such PHDs bind to N-terminal tails
of histone H3, discriminating between those methylated
(H3K4me3) or unmodified (H3K4) at Lys4. AIRE PHD1 is
most closely related to the BHC80 PHD that interacts selectively
with the unmodified H3K4 (42). Indeed, AIRE PHD1 also
binds to the unmodified H3K4 (Fig. 1A), and this interaction is
required for AIRE to activate transcription of genes in chromatin (26, 30, 37). The AIRE PHD2 sequence is divergent and
does not interact with nucleosomes, but it contributes structurally to the activation of TRA genes by AIRE (27, 31, 43).
AIRE PHD1 also binds to the DNA-dependent protein
kinase (DNA-PK) (Fig. 1A) (44). DNA-PK is a nuclear kinase, which not only functions to repair DNA double-strand
breaks and mediate V(D)J recombination, but it also supports
transcription and chromatin remodeling (45). DNA-PK also
phosphorylates two sites in the N terminus of AIRE (44).
However, pharmacological inhibition of DNA-PK and bringing AIRE to a promoter via heterologous DNA tethering in
cells lacking DNA-PK revealed that the kinase activity of
DNA-PK is dispensable for gene activation by AIRE. Instead,
these interactions represent a key mechanism for the recruitment of AIRE to its target genes (26). An important aspect of
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FIGURE 1. AIRE protein domains, key interacting partners, and mechanism of TRA gene expression. (A) AIRE contains several domains that are related to
those in other transcription factors. From the N terminus they are: HSR (green), which is important for the oligomerization of AIRE and may function as
a caspase recruitment domain (58); SAND (green); PHD1 and PHD2 (violet); proline-rich region (PRR; orange); and the TAD (red). Protein residues corresponding to human AIRE are labeled above, and the position of the four LXXLL motifs is marked below the diagram. The location of the nuclear localization
signal is also indicated (KRK). Mutations discussed in this review are marked with an asterisk below the diagram with accompanying labels. Arrows depict
interactions between DNA-PK, H3K4, P-TEFb, and AIRE. (B) Schematic diagram depicting the molecular mechanism of AIRE-regulated TRA gene expression.
Combinatorial interactions between AIRE, unmodified H3K4 (yellow), DNA-PK (red), and RNAPII (blue) recruit AIRE to a TRA promoter. AIRE brings PTEFb (red) to phosphorylate the RNAPII CTD, and this results in transcription elongation, mRNA processing, and TRA gene expression. Histone H2AX with
phosphorylated Ser139 (gH2AX), which marks DNA double-strand breaks, is depicted in yellow. (C) The Venn diagram marks sets of genes that contain unmodified H3K4, engaged RNAPII, and DNA-PK at their promoters. AIRE is targeted to and can regulate expression of genes at the intersection of these sets.
The Journal of Immunology
TEFb (28), thereby further enhancing the expression of TRA
genes to optimize the establishment of central tolerance.
Conclusions
AIRE is a transcription factor that activates the expression of
TRA genes in mTECs. Their promoters must be occupied by
RNAPII, unmodified H3K4, and DNA-PK. Sufficient levels
of these proteins ensure that AIRE is recruited to these sites.
AIRE oligomers then bring P-TEFb to RNAPII, which leads
to its extensive phosphorylation. Thus modified, RNAPII is
competent for elongation and cotranscriptional processing of
target genes, which leads to the expression of TRAs and their
presentation to T cells via MHC class II determinants.
Disclosures
The authors have no financial conflicts of interest.
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associated with the histone variant H2AX phosphorylated at
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AIRE contains four LXXLL motifs, two in the HSR, one in
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TAD (Fig. 1A). LXXLL motifs are known to mediate protein–protein interactions between nuclear receptors and their
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chromatin targeting strategies of AIRE, we can now propose
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BRIEF REVIEWS: MECHANISM OF AIRE FUNCTION