Biochem. J. (2011) 433, 1–9 (Printed in Great Britain)
1
doi:10.1042/BJ20101058
REVIEW ARTICLE
The Golgi apparatus: an organelle with multiple complex functions
Cathal WILSON*, Rossella VENDITTI†, Laura R. REGA†, Antonino COLANZI*†‡, Giovanni D’ANGELO† and
M. Antonietta DE MATTEIS*†1
*Consorzio Mario Negri Sud, Via Nazionale, Santa Maria Imbaro (Chieti) 66030, Italy, †Telethon Institute of Genetics and Medicine (TIGEM), Via Pietro Castellino 111, Naples 80131,
Italy, and ‡Institute of Protein Biochemistry (IBP), CNR, Via Pietro Castellino 111, Naples 80131, Italy
Remarkable advances have been made during the last few decades
in defining the organizational principles of the secretory pathway.
The Golgi complex in particular has attracted special attention due
to its central position in the pathway, as well as for its fascinating
and complex structure. Analytical studies of this organelle have
produced significant advances in our understanding of its function,
although some aspects still seem to elude our comprehension. In
more recent years a level of complexity surrounding this organelle
has emerged with the discovery that the Golgi complex is involved
in cellular processes other than the ‘classical’ trafficking and
biosynthetic pathways. The resulting picture is that the Golgi
complex can be considered as a cellular headquarters where
cargo sorting/processing, basic metabolism, signalling and cellfate decisional processes converge.
INTRODUCTION
dynamics, calcium homoeostasis, and PM (plasma membrane)receptor-initiated and organelle-autochthonous signalling events
that respond to growth signals and energy status. A paradox we are
experiencing in the field is that, concomitantly with uncovering
so many diverse and unpredicted functions of the GC, we are still
left with many open questions about the mechanisms governing
the ‘classical’ trafficking functions of the GC in the secretory
pathway.
In the present review we provide a brief overview of the
recent developments regarding the ‘classical’ functions of the GC
in transport and processing and discuss in more detail the other
functions that contribute to a ‘global’ understanding of the
molecular physiology of the Golgi complex.
The GC (Golgi complex) is a central organelle in the endomembrane system whose origin dates back to the last
common eukaryotic ancestor [1]. Despite its ancient origin and
the conservation of many of the Golgi-associated proteins, the
structure of the GC varies in different organisms. In most the
Golgi is arranged as a stack of flattened membrane structures
(cisternae) ordered in a polarized (cis-to-trans) fashion. However,
whereas in mammalian cells the stacks are laterally linked to form
a ribbon-like membrane system [2], in plants, invertebrates and
fungi the Golgi stacks exist as isolated entities [3,4]. In addition, in
some developmental stages of Drosophila melanogaster no stacks
are observed [4], whereas in the yeast Saccharomyces cerevisiae
the diverse Golgi cisternae exist as separate compartments
distributed throughout the cell [5,6]. Although this variability
raises the question as to whether and how the structure of the GC
is correlated with its functions, it also suggests the possibility that
the higher complexity of the structure of the GC in vertebrates,
and particularly in mammals, is required to accomplish more
complex functions that the organelle has gradually gained during
evolution.
Indeed, the last two decades have witnessed an explosion in the
number of studies that have brought to light an increasing number
of functions that converge at the GC and that add to the known and
conserved functions of this organelle in biosynthetic and secretory
pathways. These ‘novel’ functions of the GC are so numerous and
diverse as to make this organelle an active component of cellular
pathways controlling mitotic entry, cytoskeleton organization and
Key words: calcium homoeostasis, Golgi complex, mitotic entry,
Ras, signalling, Src.
A TRANSPORT AND SORTING STATION
The Golgi has a well-established role as a processing and
sorting station in the transport of transmembrane and soluble
cargo proteins to their final destinations. Various aspects of
these processes have been dealt with in detail in recent reviews
[7–9], so we provide only a brief overview of these Golgi
functions.
The GC receives neosynthesized proteins and lipids from the
ER (endoplasmic reticulum). Trafficking between the ER and
the GC involves the vesicular coat complexes COPII (coatamer
protein II), which mediates the concentration of secretory cargoes
into anterograde transport carriers, and COPI (coatamer protein
I), which recycles material from post-ER membranes back to the
ER [7]. Proteins are exported from the ER at specialized exit
Abbreviations used: AKAP450, a kinase anchor protein 450 kDa; ATF6, activating transcription factor 6; CDK1, cyclin-dependent kinase 1; CERT,
ceramide transport protein; COPI, coatamer protein I; COPII, coatamer protein II; CtBP, C-terminal-binding protein; EGF, epidermal growth factor; ER,
endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment; ERK, extracellular-signal-regulated kinase; FAPP2, four-phosphate adaptor protein
2; GC, Golgi complex; GEF, guanine-nucleotide-exchange factor; GlcCer, glucosylceramide; GM130, Golgi marker 130; GOLPH3, Golgi phosphoprotein
3; GRASP, Golgi reassembly stacking protein; GSL, glycosphingolipid; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MT, microtubule;
OSBP1, oxysterol-binding protein 1; PI, phosphoinositide; PI4K, PI 4-kinase; PI4P , PI 4-phosphate; PLK, polo-like kinase; PM, plasma membrane; RasGRP1,
Ras guanyl-releasing protein 1; RKTG, Raf kinase trapping to Golgi; SPCA, secretory pathway Ca2+ -ATPase; SREBP, sterol-regulatory-element-binding
protein; SCAP, SREBP-cleavage-activating protein; TGN, trans -Golgi network; TOR, target of rapamycin; TORC1, TOR complex 1; VPS74, vacuolar protein
sorting 74; UPR, unfolded protein response.
1
To whom correspondence should be addressed (email [email protected]).
c The Authors Journal compilation c 2011 Biochemical Society
2
C. Wilson and others
sites. In mammalian cells the transport carriers subsequently fuse
to form, or fuse with, a network of vesicular tubular clusters also
known as the ERGIC (ER–Golgi intermediate compartment). The
ERGIC appears to be a major sorting centre where many proteins
that need to be recycled via COPI-mediated retrograde transport
to the ER are separated from cargo that is destined to traverse the
GC. The segregated cargo-containing domains may then form
the cis-Golgi network or they may fuse with an already existing
cis-Golgi. As can be deduced from the above, it is still unclear
whether the ERGIC represents a stable compartment or if
it is a structure that is continuously formed and consumed
by the membrane trafficking between the ER and the Golgi
[10,11].
Having reached the Golgi the cargo molecules must traverse
anything from three to eight cisternae where they are subjected
to further processing (mainly glycosylation) that is necessary for
either the final functional form of the protein or to direct it to
the correct intra- or extra-cellular destination (see below). The
mechanism that mediates the transport of cargo through the Golgi
has been a matter of debate for years. One view (the vesicular
transport model) envisaged each cisterna as a stable entity while
the cargo is transported in an anterograde manner via COPI
vesicles that bud from one cisterna and then fuse with the next
one. However, the finding that COPI has a major role in retrograde
transport and that large cargo molecules, in spite of their inability
to fit into COPI vesicles, progress through the Golgi cisternae [12]
led to a reconsideration and an alternative model for intra-Golgi
transport, the cisternal maturation model. In this model, which
is presently the most accepted [8], cargo is maintained within a
cisterna that changes its composition (matures) by the retrograde
movement of cisternal components (enzymes and lipids) thus
achieving the identity of the foregoing cisterna [9]. Strong support
for this model came from the visualization of Golgi-resident
proteins in living yeast cells, which showed a dynamic transition
from cis-to-trans compartmental identity [13–15]. Despite this,
a full description of how cisternal maturation might operate and
of the precise role of COPI vesicles is still missing and further
clarification is needed to explain the mechanisms underlying
Golgi trafficking.
Having traversed the Golgi, the cargo molecules are sorted at the
TGN (trans-Golgi network) to various cellular destinations. This
is arguably the most complex area of the Golgi, where a multitude
of processes are integrated to provide fidelity of processing
and sorting. Final modification of glycosylated proteins (see
below) and protease cleavage of proteins to their mature form
[14] occurs here before their segregation into tubular/vesicular
carriers [16] that transport the cargo to the apical or basolateral
membranes, or to endosomal/lysosomal compartments. A review
[17] has a detailed description of the processing and sorting at the
TGN.
Although the GC represents an obligatory station for most
secreted proteins, a number of proteins reach the cell surface
by by-passing the Golgi in what is known as unconventional
trafficking, a process that appears to occur in all organisms
[18]. What, if any, type of cross-talk might exist between
these pathways provides an interesting area of study for
the future. In the present review we have only touched on the
remarkable feat of organization that operates at the Golgi
in transporting and sorting cargo, details of which can be
found in the reviews cited above. However, the GC appears to
have a much broader range of functions that regulate cellular
homoeostasis, through the control of cellular pathways that
mediate protein and lipid biosynthesis, mitotic entry, calcium
homoeostasis and PM receptor-initiated/organelle-autochthonous
signalling systems, which we describe in more detail below.
c The Authors Journal compilation c 2011 Biochemical Society
A PROTEIN AND LIPID BIOSYNTHETIC CENTRE
Cargo proteins and lipids are subjected to extensive covalent
modifications, which are coupled to their transport through and
out of the GC [19]. The net result of this activity is to create a
number of biological gradients where post-Golgi compartments
are enriched in processed compounds while pre-Golgi membranes
are enriched in precursors and immature forms.
Proteins and lipids are substrates for N-linked and O-linked
glycosylation and oligosaccharide-chain-processing at the GC
[19]. N-linked glycosylation starts in the ER, whereas further
remodelling occurs following export to the GC. Complex oligosaccharides are generated when the original N-linked
oligosaccharide is trimmed in the GC and additional sugars
are added. The trimming of mannose residues and the stepwise
addition of N-acetylglucosamine, galactose, sialic acid and, in
some cases, fucose residues occurs in an organized sequence
during protein passage through the GC. The order of enzymatic
reactions is mirrored by the sub-Golgi distribution of the
processing enzymes [20] with early (i.e. mannose removal and
N-acetylglucosamine addition) and late (i.e. galactose, sialic acid
and fucose addition) reactions being catalysed by enzymes located
in the proximal and distal regions of the GC respectively [21,22].
The enzymes responsible for glycosylation in the GC are
most frequently type II integral membrane proteins with a
C-terminal luminally oriented enzymatic domain, a stem region
and a transmembrane domain followed by a short N-terminal
cytosolic domain [19]. Although a comprehensive picture of the
mechanisms by which different enzymes localize to subdomains
of the GC is still missing a number of molecular determinants are
known to be involved in controlling the sub-Golgi distribution
of the different enzymes, including protein-binding motifs in
their cytosolic portion {e.g. to the COPI coatomer or to VPS74
(vacuolar protein sorting 74)/GOLPH3 (Golgi phosphoprotein 3);
see below and [19,23]}, interaction with the COG (conserved
oligomeric Golgi) machinery [24], homo/hetero-oligomerization
[25], partitioning into lipid domains [26,27], and transmembrane
domain length and composition [26].
The mechanisms that fine tune the activities of the glycosylating
enzymes also remain undefined, although previous findings
indicate that the glycosylation process and machinery at the GC
play an important role in integrating nutrient-sensing with cell fate
determination. A connection between protein glycosylation and
the metabolic flux to N-glycan biosynthesis has been established
and modelled [28]. Glycan chains are more branched in highnutrient conditions and this has an impact on their interaction
with galectins and prolongs the time glycoproteins are exposed at
the cell surface by decreasing their endocytosis. In addition, the
glycoproteins respond to increasing hexosamine levels according
to the number of their N-glycosylation sites. Glycoproteins with
many glycosylation sites rapidly increase at the cell surface,
whereas those with few sites follow a sigmoidal kinetic preceded
by a lag phase. As growth-promoting PM receptors are often rich
in glycosylation sites, whereas growth-antagonizing receptors
tend to bear less glycosylation sites, the authors of that study
[28] speculate that moderate fluxes of nutrients will favour cell
growth, whereas further increases will produce a shift towards
growth arrest and differentiation.
Furthermore, it has been shown recently that the distribution of
O-glycosylation enzymes is sensitive to growth factor stimulation.
This stimulation causes a subset of O-glycosylation enzymes to
translocate from the GC to the ER (see below and Figure 1),
thus increasing O-glycosylation levels that may in turn influence
cell–cell and cell–ECM (extracellular matrix) interaction
[29].
The Golgi complex
In spite of the remaining uncertainties, the importance of
the glycosylation occurring at the GC is definitively underscored by the severe consequences of human genetic diseases
caused by mutations in glycosylating enzymes, as well as
in the dedicated trafficking machineries responsible for their
intracellular distribution [30].
Another class of compounds that is glycosylated at the GC
are the sphingolipids, which include sphingomyelin and GSLs
(glycosphingolipids) [31]. When transported to the GC, ceramide,
the common sphingolipid precursor that is synthesized in the
ER, can either be processed to sphingomyelin via the addition
of a phosphocholine headgroup or be glycosylated to GlcCer
(glucosylceramide) on the cytosolic leaflet of the cis-Golgi. Once
produced and translocated into the lumen of the GC, GlcCer can
be further glycosylated to different classes of complex GSL (such
as gangliosides and globosides), depending on the nature of sugars
added to the GlcCer backbone [31].
The sphingolipid metabolic pathway has recently attracted new
interest as it has uncovered a novel paradigm of transport to and
through the GC. This is the non-vesicular transport of ceramide
and GlcCer that is mediated by the lipid transfer proteins CERT
(ceramide transport protein) and FAPP2 (four-phosphate adaptor
protein 2) respectively [32–34]. CERT mediates the non-vesicular
transport of ceramide from the ER to the late GC, where ceramide
is converted into sphingomyelin [32]. The pool of ceramide escaping CERT-mediated transport is inserted into membrane-bound
carriers and transported to the cis-Golgi where it is converted into
GlcCer. GlcCer is in turn subjected to non-vesicular transport
mediated by FAPP2, which fosters complex GSL production
on later Golgi compartments [33]. In addition to their lipid
transfer activities, both CERT and FAPP2 also participate in
secretory cargo transport from the GC to the cell surface [35–37].
Thus, by coupling sphingolipid processing with transport out of
the GC, these proteins contribute to one of the key functions
of the GC, namely the generation of asymmetry in lipid distribution in the cell membranes with late and post-GC compartments
enriched and pre- and early Golgi compartments depleted in
sphingolipids [38]. A similar consideration is also applicable to
the two cholesterol transfer proteins OSBP1 (oxysterol-binding
protein 1) and ORP9 (oxysterol-binding protein-related protein
9), which are thought to mediate cholesterol transport from the
ER directly to the trans-Golgi, and, by so doing, to contribute to
the enrichment of cholesterol in post-GC compartments [39].
AN MT (MICROTUBULE) NUCLEATION CENTRE
The structure and the positioning of the mammalian Golgi
ribbon next to the centrosome requires an intact MT and actin
cytoskeleton [40]. Treatment of cells with the MT-depolymerizing
agent nocodozole causes the breakdown of the GC into functional
mini-stacks in the vicinity of ER exit sites [41]. Indeed, the
centrosome is the major MT nucleation and anchorage centre in
cultured animal cells. Generally, the MTs are organized in radial
arrays with their minus ends anchored to the centrosome and the
plus ends directed toward the cell periphery. This population of
MTs requires γ TuRC (γ tubulin ring complex) complexes and
the large scaffold protein AKAP450 (a kinase anchor protein
450 kDa) for their nucleation [42]. MTs that are nucleated at
the centrosome form the tracks along which the Golgi stacks
are transported to the pericentriolar region through the activity
of the minus-end-directed motor dynein, and interfering with its
function by overexpressing p50 dynamitin or the CC1 domain
of p150Glued results in dispersed Golgi stacks in the cytosol
[43].
3
Importantly, the GC not only depends on MT organization but
is also able to nucleate two different classes of MTs. A subset
of Golgi-nucleated MTs are involved in the cohesion of the
stacks into a larger ribbon structure. The other subset extends
asymmetrically towards the leading edge of a migrating cell
[43]. The ability of Golgi membranes to nucleate MTs requires
AKAP450, which in turn is recruited to cis-Golgi membranes
by binding to GM130 (Golgi marker 130) [44]. This GM130dependent Golgi-localized AKAP450 regulates MT nucleation
and cell migration in a centrosome-independent manner [44].
These Golgi-nucleated MTs are coated with CLASP [CLIP
(cytoplasmic linker protein)-associated proteins], a class of MT
plus-end binding protein that promotes the stabilization of
dynamic MTs [43], and are preferentially oriented towards the
leading edge in motile cells.
Therefore, as proper organization of MT arrays is essential
for intracellular trafficking and cell motility, the Golgi-originated
MTs could contribute to the asymmetric MT networks in polarized
cells and support diverse processes including post-Golgi transport
to the cell front, a function that is essential for directional cell
motility and cell polarization.
AN AGONIST-SENSITIVE CALCIUM STORE
Although the ER is the major agonist-sensitive intracellular Ca2+
store, it is now clear that the GC can also release Ca2+ during
agonist stimulation and can contribute to the duration and pattern
of intracellular Ca2+ signalling [45,46]. Interestingly, in addition
to responding to extracellular stimuli, the GC can also release Ca2+
in response to the arrival of secretory cargo from the ER, as shown
recently by the release of Ca2+ measured during synchronized
waves of transport from the ER to, and through, the GC [47].
The GC actively captures Ca2+ reaching a high Ca2+ content
(>10 mmol/l) via two classes of Ca2+ pumps: the SERCAs
(sarcoplasmic/endoplasmic reticulum Ca2+ -ATPases) and the
SPCAs (secretory pathway Ca2+ -ATPases), which also capture
Mn2+ . The critical role of SPCA1 as a Ca2+ and Mn2+ pump
is highlighted by the observation that haplo-insufficiency of
human SPCA1 results in Hailey–Hailey disease, a skin disorder
characterized by keratinocyte cell adhesion defects [48,49]. Ca2+
sequestered into the Golgi lumen is buffered by different
Ca2+ -binding proteins, such as CALNUC, Cab45 and P54/NEFA.
The release of Ca2+ from the GC, which involves both IP3
(inositol trisphosphate)-dependent and -independent channels,
may serve different functions. First, Ca2+ regulates trafficking
in different parts of the secretory pathway, such as ER-toGolgi, intra-Golgi and Golgi-to-PM transport, by controlling
a series of trafficking machineries, such as COPII, COPI and
cPLA2 (cytoplasmic phospholipase A2 ). Secondly, changes in
luminal Ca2+ may affect Ca2+ -dependent luminal processes,
such as processing and the sorting pattern of PM proteins
(receptors, channels and enzymes). Finally, the Ca2+ released from
the GC may participate in ‘local’ organelle and interorganelle
signalling, in particular with those organelles that have a close
spatial relationship with the GC, such as secretory granules and
mitochondria.
A SIGNALLING PLATFORM
In addition to the well-documented PM-located signalling
pathways, signalling from various endomembrane locations
appears to be widespread [50]. The presence of various
elements of signal transduction cascades on the GC has been
documented for a number of years. The demonstration that truly
c The Authors Journal compilation c 2011 Biochemical Society
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Figure 1
C. Wilson and others
Ras and Src signalling at the GC
Top section (minus growth factors): in the absence of growth factors RKTG binds Raf
and inhibits MAPK activation. Bottom section (plus growth factors): the classical growth
factor-induced Ras/Raf/MAPK signal transduction pathway leads to phosphorylation of cytosolic
and nuclear substrates. Activation of Ras signalling on the Golgi by the same signal occurs
later and depends on a Ca2+ -dependent recruitment of the Ras GEF RasGRP1 to the Golgi.
Growth factors stimulate the retrograde transport of O-glycosylation enzymes (GalNac-Ts;
N-acetylgalactosaminyltransferases) from the Golgi to the ER in a Src- and COPI-dependent
manner. Top and bottom sections: cargo arrival from the ER leads to KDEL receptor (KDELR)
activation of Src on the Golgi and is required for efficient intra-Golgi transport. N, nucleus
PLCγ , phospholipase Cγ .
Golgi-localized signalling events exist has been complicated as
they share many of the molecular elements that are involved in
classical PM-initiated cascades. However, recent evidence has reenforced the idea that the GC can act as a platform for regulating a
variety of cellular functions via signalling (see Figures 1–3). Such
signalling events could be involved in GC function (structure and
trafficking) or act as part of a relay system for signals derived
from other intra-organellar structures or from the PM. In addition
to signals arriving at the GC to initiate a response, the signal
transduction cascade could be initiated within the GC itself.
A relay station for PM-initiated signalling
The classical Ras/MAPK (mitogen-activated protein kinase)
signalling pathway is triggered at the PM by the activation of
various receptors and affects many important cellular functions
[51]. However, Ras-mediated signalling has also been described
on endomembrane systems including the endosomes, ER and
the GC. GTP-bound Ras accumulates on the GC in response to
growth factor signalling as shown by the recruitment of a GFP
(green fluorescent protein)–Raf-1-RBD (Ras-binding domain)
reporter that has a high affinity for activated Ras [52]. Ras
activation, indeed, may occur in situ on the GC as a Ras GEF
(guanine-nucleotide-exchange factor), RasGRP1 (Ras guanylreleasing protein 1), is recruited to the GC upon EGF (epidermal
growth factor) stimulation in a Ca2+ -dependent fashion [53]
(Figure 1). Activation of Ras at the GC does not require vesicular transport and occurs subsequently to Ras signalling at the
PM that is switched off by the Ca2+ -dependent recruitment of
the Ras GAP (GTPase-activating protein) CAPRI (Ca2+ -promoted
Ras inactivator) [53]. Therefore the same second messenger, i.e.
Ca2+ , is co-ordinating the shutdown of one signalling event while
activating another at a different cellular location.
c The Authors Journal compilation c 2011 Biochemical Society
Interestingly, the targeting of Raf to different Ras nanoclusters
at the PM and at the GC results in differential MAPK outputs
[54]: whereas signalling at the PM responds to signal inputs
with maximal MAPK output, the Golgi-localized signalling is
graded and occurs at a later time than the PM activation.
Compartmentalized signalling of Ras at the GC or the PM,
depending on the stimulus, in mammalian cells can also
determine the physiological outcome [55,56]. Differential PM and
endomembrane signalling via Ras also occurs in the fission yeast
Schizosaccharomyces pombe where Ras1p signalling controls
two distinct pathways: Ras1p-mediated signalling at the ER
controls cell morphology, whereas that at the PM drives mating
[57].
Although there is still some controversy about the in situ
activation of Ras at the GC [58] it has been proposed that
active Ras at the GC could control the spatio-temporal assembly
in this compartment of the active MEK/ERK/SEF complex,
[where ERK is extracellular-signal-regulated kinase and SEF is
similar expression to FGF (fibroblast growth factor), a MAPK
scaffold] in response to mitogen stimulation [59]. Interestingly,
the MAPK activity is directed towards the cytosolic substrate
RSK2 (ribosomal S6 protein kinase 2), but blocked in its ability
to act on the nuclear substrate Elk1 (Ets-like gene 1).
Finally, the GC can also act as a negative regulator of
signalling pathways as in the case of RKTG (Raf kinase
trapping to Golgi), a seven-transmembrane protein localized at
the GC, which sequesters Raf-1 from the cytoplasm, blocks EGFstimulated Raf-1 membrane translocation, reduces the interaction
of Raf-1 with Ras and MEK1 and, by inhibiting the ERK
signalling pathway, blocks NGF (nerve growth factor)-mediated
PC12 cell differentiation [60] (Figure 1).
These results point to an interesting paradigm where the type,
duration and strength of the signal originating at the PM can
be transduced into different physiological outcomes that depend
on the physiological context and rely on compartmentalized
signalling from endomembrane platforms. Although as yet there
has been no direct demonstration that oncogenic Ras might
function at this level, the above-mentioned effects of Ras targeting
to the Golgi or the ER open up this possibility. Indeed, various
forms of cancer have been linked to signalling via proteins mistargeted to the Golgi or defects in Golgi-associated proteins
(Table 1).
A node in signalling pathways controlling lipid homoeostasis, ER
stress response and nutrient sensing
Lipid homoeostasis
Lipid homoeostasis is intimately associated with intracellular
membrane trafficking [61]. Intracellular signalling via the Golgi
has been elegantly demonstrated by analysis of the sterolsensing signalling pathway involving SREBPs (sterol-regulatoryelement-binding proteins), transcription factors that target genes
involved in lipid synthesis. There are three SREBPs, with SREBP1a and -1c representing alternative transcripts, and with
SREBP-2 encoded by a separate gene. SREBP-1c appears
to control fatty acid synthesis, whereas SREBP-2 controls
cholesterol synthesis [62]. High levels of sterols maintain SREBPs
as inactive precursors in the ER where they are bound by SCAP
(SREBP-cleavage-activating protein), which interacts with the
ER resident INSIG (insulin-induced gene) and blocks interaction
with the COPII vesicle coat. When sterols levels are low, SREBP–
SCAP is transported to the GC where a two-step proteolytic
cleavage releases the mature form of SREBP, which then
translocates to the nucleus where it binds to sterol-response
The Golgi complex
Table 1
5
Oncogenes and the GC
Activation of the proto-oncogene Ras on the Golgi can lead to cell transformation [53]. The proto-oncogene Src is activated on the Golgi [87] but to date there has been no demonstration that
Src mutations lead to oncogenesis via Golgi signalling. The KIT(D816V)-activating mutation of the receptor tyrosine kinase proto-oncogene c-KIT may be blocked in a constitutively active form
on the Golgi and has transforming activity [101]. The GC-associated protein FIG (fused in glioblastoma), fused with the kinase domain of the proto-oncogene, c-ROS localizes to the Golgi and
results in constitutive kinase activation and oncogenic transformation [102]. Amplification of the Golgi protein GOLPH3 is associated with human cancer by enhancing growth-factor-induced mTOR
(mammalian TOR) activity [103]. MAPK-mediated constitutive localization of ATF6 to the nucleus is required for the prolonged survival of dormant but not proliferative carcinoma cells [104].
Overexpression of the RKTG protein can sequester oncogenic B-Raf to the Golgi and have a suppressive role in human melanoma by inhibiting Raf-dependent ERK activation, cell proliferation and
transformation [105].
Gene
Defect
Effect
Ras
Src
c-KIT
c-ROS
GOLPH3
ATF6
RKTG
Artificially directing Ras or Raf to endomembranes
No Golgi-associated relationship with cancer described
Constitutively active mutated receptor tyrosine kinase on the Golgi
Genomic rearrangement FIG–ROS targeted to Golgi
Genomic amplification
Constitutive nuclear localization
Overexpression sequesters oncogenic B-Raf to the Golgi
Transforming activity
–
Transforming activity
Oncogenic transformation
Associated with human cancer
Prolonged survival of dormant but not proliferative carcinoma cells
Suppressive role in human melanoma
cells to maintain the correct levels of chaperones and regulate
folding for the efficient transport of cargo proteins [67].
Why the above transcription factors have to be transported
through the Golgi for activation is presently unclear. One
possibility is that this Golgi passage tests and ‘signals’ that there
is a functioning transport system, thus avoiding gene transcription
and toxic levels of proteins and lipids that could not be transported
to their correct destination. Alternatively, this spatial separation
might avoid the inappropriate cleavage of SREBPs during mitosis
as they are maintained in separate compartments after Golgi
fragmentation [68].
Nutrient sensing
Figure 2 The GC as a node in signalling pathways controlling lipid
homoeostasis and the ER stress response
SREBPs are transported from the ER to the Golgi, proteolytically cleaved by the Site 1 and Site
2 proteases (P1S and P2S) and the mature form translocates to the nucleus (N) to activate
transcription. Under glucose-replete conditions (bottom section) TOR activity is required for
SREBP-1, but not SREBP-2, activity (where exactly this input occurs is unknown). This SREBP-1
activity is inhibited in low-glucose conditions (top section) while SREBP2 activity is blocked by
the binding of the ER-stress transcription factor ATF6. ATF6-dependent transcription is, however,
enhanced under low-glucose conditions.
elements in the promoters of multiple target genes [63,64]
including those involved in sterol synthesis (Figure 2).
The control of cell growth and metabolism in response to nutrients
and growth factors is operated by TOR (target of rapamycin) [69],
a highly conserved serine/threonine kinase that has also been
found to be associated with the ER and the Golgi [70]. Notably,
TOR mediates SREBP-1 (but not SREBP-2) translocation to the
nucleus in a manner that depends on the presence of glucose
[71]. Low glucose levels block SREBP-1 activation and lead
to inhibition of nuclear SREBP-2 by ATF6. In fact glucose
deprivation may result in an ER stress response where the
cleaved ATF6 binds the cleaved SREBP-2 transcription factor
thus inhibiting lipogenesis [72] (Figure 2).
Nutrient limitation in yeast leads to TOR-mediated
translocation of the transcription factor Gln3p from the
TGN/endosome compartment to the nucleus, a translocation that
requires Golgi-to-endosome trafficking [73,74]. TORC1 (TOR
complex 1) in yeast has been localized to the Golgi and endosomal
compartments [75,76], and mutation of Lst8p, a TORC1 protein,
also results in the mislocalization of Gln3p to the nucleus [77].
UPR (unfolded protein response)
ATF6 (activating transcription factor 6), a master regulator of the
UPR, also requires transport from the ER to the Golgi where
it is cleaved by the same proteases that act on SREBPs before
translocation to the nucleus, where it activates expression of the
ER stress-response genes [65]. Release from the ER and transport
to the Golgi requires ATF6 dissociation from the ER chaperone
BiP (binding immunoglobulin protein) and interaction with the
COPII complex for inclusion into ER-to-Golgi carriers [66]. In
the absence of the site 2 protease, ATF6 is retained in the Golgi
and transcription of the stress-response genes is blocked [67].
The ATF6-responsive mechanism may also function in unstressed
A centre for integrating cell growth and trafficking
The GC is an active PI (phosphoinositide)-metabolizing centre
[78]. Among the PI-metabolizing enzymes that are particularly
relevant for their role at the GC are PI4KIIIβ (phosphoinositide 4kinase class IIIβ) and its yeast homologue Pik1p that synthesizes
PI4P (phosphoinositide 4-phosphate). They control TGN-to-PM
transport of newly synthesized cargo and the structure of the GC
itself [79–81].
Interestingly, the balance between synthesis (by PI4Ks) and
removal (by the PI4P phosphatase Sac1p) of PI4P at the GC
varies depending on nutrient availability and growth stage.
c The Authors Journal compilation c 2011 Biochemical Society
6
Figure 3
C. Wilson and others
PI4P at the GC integrates cell growth and membrane trafficking
Bottom section (high glucose): high levels of PI4P , required for Golgi structure and efficient
transport, are maintained by the action of the kinase Pik1 (PI4KIIIβ in mammals) at the Golgi,
and the retention of the PI4P phosphatase Sac1 in the ER under glucose-replete conditions
(in yeast) or mitogen stimulation (in mammals). In mammals Sac1 is returned to the ER
following the re-addition of mitogens to quiescent cells in an MAPK-dependent manner. Top
section (low glucose): in low glucose, Sac1 is transported to the Golgi complex and Pik1
dissociates from the Golgi, being sequestered by 14-3-3 proteins leading to low Golgi PI4P
levels. N, nucleus. An animated version of this Figure is available at http://www.BiochemJ.
org/bj/433/0001/bj4330001add.htm
Under nutrient-replete conditions in yeast Sac1p is localized
to the ER but upon glucose starvation or in quiescent cells
it translocates to the GC where it reduces the levels of PI4P
thus inactivating trafficking [82]. Upon glucose re-addition or
mitogenic stimulation Sac1p shuttles back to the ER via a
COPI-mediated mechanism (Figure 3). In mammalian cells this
relocation of Sac1 to the ER relies on the dissociation of Sac1
oligomers at the TGN and requires the p38 MAPK (Figure 3). In
stationary-phase yeast cells or after glucose depletion this Sac1p
shuttling is accompanied by a dissociation of Pik1p and Frq1p (a
non-catalytic subunit required for Pik1p localization on the GC),
away from the GC to the cytoplasm in a manner that depends
on binding to 14-3-3 proteins and that contributes to lower PI4P
levels at the GC [83] (Figure 3).
The levels of PI4P control the recruitment/activation of many
proteins that regulate Golgi structure and function. These include
the AP1 (adaptor protein 1), the lipid transfer proteins FAPP2,
CERT and OSBP1 (reviewed in [78]) and VPS74/GOLPH3
[84,85]. In particular VPS74 is required for retrograde trafficking
of Golgi enzymes and for their steady-state localization in yeast
[23,84]. In mammals GOLPH3 can bind to MYO18A (myosin
XVIIIA) thus linking the Golgi to actin filaments. The resulting
tensile force may be required for the formation of the Golgi
ribbon and for efficient post-Golgi carrier formation [85]. Finally,
GOLPH3 is an oncogene amplified in some human cancers
(Table 1), but exactly how this relates to the interactions described
above, including those with PI4P, remains to be clarified.
‘Signalling from the inside’
In addition to signalling at the GC in response to extracellular
stimuli, or to variations in growth or nutrient conditions, as
described above, the GC can also generate ‘autochthonous’
signalling in response to the arrival of cargo from the ER. It
c The Authors Journal compilation c 2011 Biochemical Society
has been well-documented that ER chaperones arriving at the
Golgi are recycled to the ER via a KDEL (Lys-Asp-Glu-Leu)
receptor/COPI-mediated mechanism [86]. It now appears that
this chaperone–KDEL receptor binding is not just for retrieval
but has an additional important function in ‘activating’ the KDEL
receptor, which then initiates the activation of a Src family
kinase phosphorylation cascade on the GC that in turn activates
and is required for intra-Golgi trafficking [87] (Figure 1). The
identification of this novel pathway thus represents a signalling
module that is initiated within the Golgi itself to regulate cargo
traffic and secretion. One possible function of this cascade is
to control Golgi dynamics and cargo exit from the TGN by
phosphorylation of the Src substrate dynamin 2 that has a role
in membrane fission [88]. Other effectors of the KDEL-receptortriggered signalling cascade at the GC remain to be determined.
Growth factors can also stimulate the retrograde transport
of a subset of O-glycosylation enzymes (N-acetylgalactosaminyltransferases) from the Golgi to the ER in a Src- and COPIdependent manner (Figure 1) although it is unclear if this depends
on the Golgi-localized Src activation [29].
The Golgi mitotic checkpoint
The mitotic inheritance of the Golgi apparatus in mammalian cells
requires the progressive and reversible disassembly of the ribbon
into dispersed small fragments. Golgi fragmentation requires the
fissioning protein CtBP3 (C-terminal-binding protein 3) [also
known as BARS (BFA-dependent ADP-ribosylation substrate)]
and the kinases MEK1, Raf1, PLK1 (polo-like kinase 1), PLK3,
VRK1 (vaccinia-related kinase 1) and CDK1 (cyclin-dependent
kinase 1) [89,90]. Some of the substrates of these kinases have
been identified and include several ‘golgins’ (i.e. GM130 and
golgin 84) and the ‘stacking factors’ GRASP65 (Golgi reassembly
stacking protein 65) and GRASP55, which are a class of Golgilocalized protein forming a complex network that organizes Golgi
structure and function [91].
The first Golgi fragmentation step occurs in the G2 phase of the
cell cycle and consists of the cleavage of the tubular non-compact
zones that interconnect the Golgi stacks into a ribbon. This ribbon
cleavage produces isolated stacks, which remain structurally and
functionally normal, and in their usual pericentriolar position
[92,93]. Importantly, the functional block of the fissioning protein
CtBP3, or of the kinase MEK1, causes the inhibition of the ribbon
severing and in the arrest of the cell cycle at the G2 stage [92,93].
Therefore these studies have revealed that the partitioning of the
GC is not passively regulated by cell-cycle transition; instead, it
is necessary for entry into mitosis [94]. This cell-cycle block is
not mediated by the activation of the well-known DNA damage
checkpoint: for this reason, the existence of a novel checkpoint
pathway that appears to sense the integrity of the GC, the ‘Golgi
checkpoint’, has been postulated [94]. These findings underscore
a regulatory interplay between organelle inheritance and the
signalling pathways that regulate cell division.
Once in mitosis, the Golgi stacks undergo further
fragmentation, which is independent of CtBP3 and MEK1,
and is controlled by CDK1 and PLK1 [90]. Interestingly, the
disassembly of the isolated stacks correlates with the release from
the Golgi membranes of a set of peripheral proteins that acquire
new roles for the completion of cell duplication. For instance,
ACBD3 (acyl-CoA-binding-domain-containing 3) is released
by Golgi membranes during mitosis and it regulates Numb
signalling, and thus represents a mechanism for coupling cell-fate
specification and cell-cycle progression [95]. In addition the
fraction of clathrin that dissociates from the GC during mitosis is
then relocated at the centrosomes, where it anchors the MT fibres
The Golgi complex
and stabilizes the mitotic spindle, a function that is essential
for proper chromosome separation [96]. As a final example,
when the peripheral Golgi protein Nir2 is phosphorylated by
the mitotic kinase Cdk1, it dissociates from the disassembled
Golgi and moves to the cleavage furrow and midbody during
cytokinesis. The phosphorylated Nir2 acts here as a docking site
for Plk1, an essential step for the completion of cytokinesis [97].
Thus, whereas the severing of the ribbon regulates the entry
into mitosis, the disassembly of the stacks can exert a regulatory
role on the progression through mitosis. Finally, a recent study has
revealed that the mitotic spindle is necessary for the reformation of
a Golgi ribbon in daughter cells [98]. Since the Golgi membranes
start to reform during cytokinesis [99], and since Golgi-derived
vesicles from both daughter cells not only traffic to the furrow
region but dock and fuse there [100], this could suggest that
correct partitioning of Golgi membranes is required for a balanced
resumption of membrane trafficking before cell abscission.
CONCLUDING REMARKS
The discovery of so many diverse processes converging at the
GC poses the question of whether and how they are controlled
by and/or control the ‘basic” functions of the GC in membrane
trafficking and sorting, and in protein and lipid biosynthesis.
Unravelling the interplay among these processes promises to
result in a more holistic picture with the expectation of shedding
light on the more obscure aspects of the physiology of the GC,
an organelle that has been attracting the interest of cell biologists
ever since its initial description.
FUNDING
The work of our laboratories is supported by Telethon Italy [grant numbers GSP08002,
GGP06166 (to M. A. D. M), GGP07075 (to C. W.)] and the Associazione Italiana per la
Ricerca sul Cancro (AIRC) [grant numbers IG 8623 (to M. A. D. M), IG 6074 (to A. C.)].
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Received 13 July 2010/29 July 2010; accepted 3 August 2010
Published on the Internet 15 December 2010, doi:10.1042/BJ20101058
c The Authors Journal compilation c 2011 Biochemical Society