Architecture of the Mammalian Golgi

Judith Klumperman
Cell Microscopy Center, Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan
100, 3584CX Utrecht, The Netherlands
Correspondence: [email protected]

Since its first visualization in 1898, the Golgi has been a topic of intense morphological
research. A typical mammalian Golgi consists of a pile of stapled cisternae, the Golgi
stack, which is a key station for modification of newly synthesized proteins and lipids.
Distinct stacks are interconnected by tubules to form the Golgi ribbon. At the entrance site
of the Golgi, the cis-Golgi, vesicular tubular clusters (VTCs) form the intermediate between
the endoplasmic reticulum and the Golgi stack. At the exit site of the Golgi, the trans-Golgi,
the trans-Golgi network (TGN) is the major site of sorting proteins to distinct cellular
locations. Golgi functioning can only be understood in light of its complex architecture,
as was revealed by a range of distinct electron microscopy (EM) approaches. In this article,
a general concept of mammalian Golgi architecture, including VTCs and the TGN, is
described.

n 1898 Camillo Golgi was the first to visual- have followed, the visualization of the Golgi
I ize, describe, and ultimately name the Golgi
complex. Using a histochemical impregnation
has gone hand-in-hand with the developing
EM techniques.
method causing the reduction and deposition The intriguing structural complexity of the
of silver, he defined the Golgi in neuronal cells Golgi has made it one of the most photograph-
as a reticular apparatus stained by the “black ed organelles in the cell. However, a full under-
reaction” (Golgi 1898). In the 1950s, the first standing of Golgi architecture is hard to deduce
ultrastructural images of the Golgi were re- from the ultrathin (70 – 100 nm) sections used
vealed using the then newly developed electron in standard transmission EM preparations.
microscope (EM) (Dalton 1954; Farquhar and Rambourg and Clermont (1974) were the first
Rinehart 1954; Sjostrand and Hanzon 1954; to investigate the Golgi in three dimensions
Dalton and Felix 1956), reviewed by Farquhar (3D), using stereoscopy (Rambourg 1974). In
and Palade (1981). In 1961, the thiamine pyro- this approach a “thick” (150 – 200 nm), EM
phosphatase reaction developed by Novikoff section is photographed at two distinct angles,
and Goldfischer allowed cytochemical label- after which the pairs of photographs are viewed
ing of Golgi membranes, which revealed the with a stereoscope. Over the years, stereoscopy
ubiquitous cellular distribution of this organ- was applied to a variety of cells and has greatly
elle (Novikoff and Goldfischer 1961). In the contributed to our current understanding
many years of ultrastructural research that of Golgi architecture (Lindsey and Ellisman

Editors: Graham Warren and James Rothman

Additional Perspectives on The Golgi available at www.cshperspectives.org
Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005181
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1
J. Klumperman

1985; Rambourg and Clermont 1990; Clermont et al. 2005; Gaietta et al. 2006; Zeuschner et al.
et al. 1994; Clermont et al. 1995). An alternative 2006; Meiblitzer-Ruppitsch et al. 2008), but
approach to study 3D structure is serial section- these have only been applied in a limited man-
ing, by which a series of adjacent (serial) thin ner to Golgi studies. Another approach that
sections are collected. The Golgi can be followed holds great potential for Golgi research is cor-
throughout these sections and be construct- relative microscopy (CLEM). Live cell imaging
ed into a 3D model (Beams and Kessel 1968; of fluorescent proteins has revolutionized cell
Dylewski et al. 1984; Rambourg and Clermont biology by the real time visualization of dy-
1990). In the nineties, 3D-EM was boosted by namic events. However, live cell imaging does
the introduction of high-voltage, dual axis 3D not reveal membrane complexity. By CLEM,
electron tomography (Ladinsky et al. 1999; live cells are first viewed by light microscopy and
Koster and Klumperman 2003; Marsh 2005; then prepared for EM (Mironov et al. 2008; van
Marsh 2007; Noske et al. 2008), which allows Rijnsoever et al. 2008). When coupled with the
the analysis of sections of up to 3– 4 mm with recent introduction of super resolution light
a 4– 6 nm resolution in the z-axis. The sections microscopy techniques for real time imaging,
are photographed in a tilt series of different the combination with EM for direct correlation
angles, which are reconstructed into a 3D tomo- with ultrastructural resolution has great poten-
gram that allows one to “look beyond” a given tial (Hell 2009; Lippincott-Schwartz and Man-
structure and reveals how it relates to other cel- ley 2009).
lular compartments. The 100th anniversary of the discovery of the
Membranes with a similar appearance can Golgi, in 1998, triggered a wave of reviews on this
differ in protein content and function. These organelle, including those focusing on Golgi
differences are revealed by protein localiza- architecture (Rambourg 1997; Farquhar and
tion techniques. Therefore, in addition to the Palade 1998). More recent reviews that describe
“classical” EM techniques providing ultrastruc- Golgi structure in great detail are provided by
tural details, EM methods that determine Marsh (2005) and Hua (2009). In this article,
protein localization within the context of the the most recent insights in mammalian Golgi
cellular morphology have been crucial to fur- architecture as revealed by distinct EM ap-
ther our understanding on the functional or- proaches are integrated into a general concept.
ganization of the Golgi. For example, by
enzyme-activity-based cytochemical staining
MAMMALIAN GOLGI ARCHITECTURE:
the cis-to-trans-polarity in the distribution of
GENERAL OVERVIEW
Golgi glycosylation enzymes was discovered,
reviewed by Farquhar and Palade (1981), which Though different methods of sample prepara-
was key to understanding the functional organ- tion and EM techniques highlight different
ization of the Golgi stack in protein and lipid morphological features, a consensus view has
glycosylation. With the development of immu- emerged over many decades describing the
noEM methods, using antibodies, the need for general organization of the mammalian Golgi
enzyme activity for protein localization was and its connected membranes (Figs. 1 and 2).
overcome. This paved the way for the localiza- A typical mammalian Golgi consists of a pile
tion of a wide variety of proteins, such as the of stapled, disk-like membranes, the cisternae,
cytoplasmic coat complexes associated with which together form the Golgi stack. Based on
the Golgi (Rabouille and Klumperman 2005). the presence of distinct sets of resident proteins,
A logical next step in EM-based imaging of the Golgi stack can be divided into three re-
the Golgi would be to combine protein locali- gions: cis, medial and trans. The cisternae move
zation with 3D imaging, but this is technically and mature from the cis- into the trans-direc-
challenging. A number of protocols enabling tion, which in parallel to other pathways of
protein localization in 3D have recently been intraGolgi transport, provides a major mode
described (Trucco et al. 2004; Grabenbauer of anterograde membrane flow (for a detailed

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 Golgi Architecture

A
Clathrin

COP I

COP II

CV
TGN

trans

Golgi stack

cis
Noncompact zone

cVTC

pVTC

ERES

ER ERES ER

B
Noncompact zone

C1 C2

Tangential view

Figure 1. Schematic representation of the Golgi and associated membrane networks. (A) Overview of the Golgi
stack in relation to ERES, central (c) and peripheral ( p) VTCs and TGN and the occurrence of COPII, COPI, and
clathrin coats. Membranes are drawn as if cross-sectioned in side view. Because of space limitations the COPI
vesicles are indicated at only one side of the Golgi stack and the noncompact zone is only drawn at the cis-
cisterna. CV ¼ condensing vacuole. (B) Tangential view of two cisternae (C1 and C2) from adjacent Golgi stacks
that are bridged by the tubular network of the noncompact zone.

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J. Klumperman

Figure 2. Golgi region of a human dendritic (D1) cell. Cells were prepared by high-pressure-freezing fixation and
freeze-substitution for examination by EM. Multiple Golgi stacks (G) are surrounded by numerous vesicles on
which the characteristic dense, regular, coatomer protein complex-I (COPI) coat is clearly visible (arrows). Sim-
ilar coats are also seen on the rims of Golgi cisternae (arrows); these COP coats are markedly different from the
more spiky and wider clathrin coat that is abundant at the trans-side of the Golgi (arrowheads). The asterisk
indicates a tangential section of a Golgi cisterna. M ¼ mitochondrion, E ¼ endosomes. Bar, 200 nm. This fig-
ure was modified from Rabouille and Klumperman (2005) and reprinted with permission from Nature Review
Molecular Cell Biology # 2005.

discussion on intraGolgi transport, see Glick vesicular tubular clusters (VTCs) mediates
and Luini 2011). A mammalian cell can contain transport between the ER and the Golgi stack.
multiple Golgi stacks that are laterally intercon- At the trans-side, the trans-Golgi network
nected by a reticulated network of branching (TGN) receives proteins that have passed
and rejoining tubules, referred to as the non- through the Golgi stack and distributes them
compact zone (Fig. 1B). The compound struc- to distinct cellular locations. The Golgi ribbon
ture of different stacks interconnected by is typically located in the perinuclear area around
tubules is called the Golgi ribbon. In addition, the microtubule organizing center (MTOC) and
the Golgi stack is closely associated with two maintenance of Golgi structure is intimately
elaborate membrane networks located at the related to both the microtubule and actin
cis- and trans-sides, which represent the en- cytoskeleton (Thyberg and Moskalewski 1985;
trance and exit faces of the stack, respectively Weidman et al. 1993; Thyberg and Moskalewski
(Fig. 1A). At the cis-side, a collection of 1999; Egea et al. 2006; Kondylis et al. 2007;

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 Golgi Architecture

Brownhill et al. 2009; Goud and Gleeson 2010). by the absence of ribosomes and the presence
In the paragraphs below the distinct components of V-shaped membrane profiles, which repre-
of Golgi architecture and its associated mem- sent the forming vesicles, and longer membrane
branes are described in greater detail. evaginations, which may be up to 500 nm in
length (Palade 1975; Sesso 1994; Bannykh et al.
1996; Fan et al. 2003; Mironov et al. 2003). In
THE CIS-FACE OF THE GOLGI
the EM, ERES are most readily found in the
All newly synthesized proteins that are destined area facing the cis-Golgi (Fig. 3B). However, de-
for secretion or intracellular compartments pending on the cargo load (Farhan et al. 2008);
enter the secretory pathway by co- or posttrans- numerous smaller ERES can arise in the periph-
lational translocation across the endoplasmic eral cytoplasm, at some distance from the Golgi
reticulum (ER) membrane. Transport of pro- (Lotti et al. 1992; Klumperman et al. 1998b).
teins out of the ER occurs by membrane- Many of the ERES budding profiles display
bounded carriers, which bud from the ER at a thin, regular coating at their cytoplasmic leaf-
specialized ER exit sites (ERES) (Figs. 1A and let, representing the COPII coat. Assembly of
3), also known as transitional elements (TEs) the COPII coat requires activation of Sar1-GDP
or transitional ER (tER). ERES are recognizable by the integral ER protein sec12, leading to

Figure 3. Interface between ER exit sites, VTCs and the Golgi stack. Human hepatoma HepG2 cells were fixed by a
mixture of formaldehyde and glutaraldehyde and prepared for ultrathin cryosectioning and immunoEM. (A)
Immunogold labeling for the VTC marker ERGIC53 (10 nm gold) shows a budding profile (arrow) on an
ER cisterna. The ERES faces a characteristic tubulovesicular VTC. (B) Double immunogold labeling for COPII
(10 nm gold) and the ER-Golgi SNARE hsec22b (15 nm gold) outlines ERES located in the central Golgi region.
Note that the membrane buds emerging from the ER (arrows) are labeled for COPII. G ¼ Golgi stack. Bars,
200 nm. Figure 3A is modified from Hay et al. (1998) and reprinted with permission from Journal of Cell Biology
# 1998. Figure 3B is modified from Klumperman et al. (1998) and reprinted with permission from Journal of
Cell Science # 1998.

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J. Klumperman

subsequent recruitment of Sec23/Sec24p and (Lotti et al. 1992; Klumperman et al. 1998b).
Sec31/Sec13p. The COPII coat then drives the Generally, the central VTC is the largest and
deformation of ER membranes into budding faces the cis-side of the Golgi, whereas the pe-
vesicles containing cargo for export from the ripheral ERES have no adjacent Golgi (Fig. 1A)
ER (Barlowe et al. 1994; Barlowe 2003). The (Balch et al. 1994; Klumperman 2000). Size
size and shape of free COPII-coated vesicles, measurements of ER-associated VTCs and those
after detachment from the ER, ranges from on their way to the Golgi suggest that small
60 nm vesicles to 200 nm tubules, often with clusters of tubulovesicular membranes detach
a halter-like appearance; that is, two balls con- from the peripheral VTCs and head toward
nected by a thinner stem (Sesso 1994; Bannykh the Golgi (Balch et al. 1994; Bannykh et al.
et al. 1996; Zeuschner et al. 2006). The COPII 1996; Klumperman 2000). This transport is
vesicles uncoat and fuse with each other or microtubule-dependent and followed by fusion
with an independent cluster of vesicular and of the peripherally derived membranes with
tubular shaped membranes, the so-called VTCs central VTC membranes or the cis-Golgi cis-
(Bannykh et al. 1996), which are also commonly terna (Presley et al. 1997; Scales et al. 1997).
referred to as ER-Golgi intermediate compart- The central VTC flattens out into small-sized
ment, ERGIC (Farquhar and Hauri 1997). cisternal membranes (Mogelsvang et al. 2004)
that deposit in parallel to the cis-most Golgi cis-
ternae. They then fuse either directly with the
Vesicular Tubular Clusters
preexisting cis-cisterna or laterally, to make a
As is indicated by their name, VTCs comprise a new cis-cisterna (Fig. 1) (Hauri and Schweizer
mixture of vesicles and tubules. Typically, VTCs 1992). Based on a computational model, it
are located adjacent to an ERES (Bannykh et al. was hypothesized that the extent by which
1996). The tubules are sometimes branched, VTC membranes can fuse with the cis-Golgi cis-
forming typical tri-angular membrane profiles. terna is determined by the rate by which the
In addition, VTCs can display a few flat disc- maturing cisterna loses its fusion competence,
like membranes (cisternae) of modest diameter, for example by recycling SNARE proteins to
which are mostly found further away from the ER (Kuhnle et al. 2010). In electron micro-
the ER (Sesso et al. 1994; Klumperman et al. graphs, providing a snapshot of these fusion
1998b) (Fig. 3A). Continuities between VTCs events, continuities between the central VTC
and ERES are very rarely seen, mostly under and the cis-Golgi are regularly observed and
nonphysiological circumstances (Bannykh et al. also referred to as the cis-Golgi network (Lind-
1998), defining the VTCs as an independent sey and Ellisman 1985; Huttner and Tooze 1989;
compartment. On VTC membranes, a second Rambourg and Clermont 1990; Pelham 1991;
type of coat assembles, the COPI coat, which Rambourg 1997).
can induce the formation of COPI-coated ves- By morphology alone, the boundary be-
icles that retrieve ER-resident proteins and tween the end of a VTC and the beginning of
membranes to the ER (Lewis and Pelham 1990; the Golgi is hard to set (Mellman and Simons
Letourneur et al. 1994). These coats consist of 1992). However, marker proteins specific for
the small GTPase ARF and a preassembled coat- VTCs, like ERGIC53, show a remarkably strict
omer complex of seven subunits (Rothman segregation between VTC and Golgi membranes
1994). Since COPII coats exclusively associate (Fig. 4A). Notably, this close relationship be-
with budding profiles forming on ER mem- tween VTCs and Golgi was first shown when
branes, whereas COPI coats are absent from Golgi’s histochemical staining method was
these ER-associated buds, the presence of COPI adapted for EM. The electron-dense staining
can be used to distinguish VTC membranes obtained by reducing osmium was specifically
from ERES (Martinez-Menarguez et al. 1999). found in the cis-most cisterna of the Golgi as
Cells can have multiple VTCs associated well as in the VTCs (Rambourg et al. 1974;
with both the central and peripheral ERES Farquhar and Palade 1981).

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 Golgi Architecture

Figure 4. Interface between the Golgi stack, VTCs and TGN. Human hepatoma HepG2 cells were fixed using a
mixture of formaldehyde and glutaraldehyde and prepared for ultrathin cryosectioning and immunoEM. (A)
Immunogold labeling for the VTC marker ERGIC53 (10 nm gold) illustrates the boundary between VTCs
and the Golgi stack (G). ERGIC53 label is restricted to the VTC membranes and cis-most cisterna of the Golgi
stack. The TGN is devoid of ERGIC-53 label. The arrowhead points to a clathrin-coated TGN membrane. (B)
Immunogold labeling for the TGN markers TGN46 (10 nm gold) and cation-independent mannose 6-
phosphate receptor (CI-MPR; 15 nm gold) outlines the cisternal and tubular membranes of the TGN. Arrow-
heads point to clathrin-coated TGN membranes. N ¼ nucleus, P ¼ plasma membrane. Bars, 200 nm. Figure
4A is modified from Klumperman et al. (1998) and reprinted with permission from Journal of Cell Science
# 1998.

THE GOLGI STACK collection of distinct stacks that are intercon-

nected by the tubular noncompact zones is
The morphologically most striking part of the referred to as the Golgi ribbon (Figs. 1 and 5)
Golgi, the Golgi stack (sometimes referred to (Rambourg et al. 1979; Rambourg 1997).
as the core region or compact zone of the Golgi), When viewed by EM, an individual cell can
consists of flat, cisternal membranes. The typical show multiple Golgi stacks, representing a sin-
structure of the Golgi stack arises because gle Golgi ribbon winding in and out of the
distinct cisternae align on top of each other, section (Rambourg et al. 1979; Marsh et al.
forming a pile of closely opposed membranes 2001a) (Fig. 2). The number of cisternae within
(Fig. 2). The diameter of the cisternae varies a stack varies between 4 and 11 in mammalian
per cell and per condition, but between distinct cells (Rambourg 1997) and is characteristic for
organisms ranges from 0.7 to 1.1 mm (Rabouille each cell type. The trans-most cisterna of the
et al. 1995; Pelletier et al. 2002). Most mamma- Golgi is unique in that it displays a third type
lian cells contain multiple Golgi stacks that are of coat i.e., in addition to COPII and COPI,
laterally interconnected with tubules, desig- the clathrin coat. This trans-most cisterna also
nated the noncompact zone of the Golgi. A gives rise to the tubular membranes of the

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J. Klumperman

Figure 5. Replica’s of isolated Golgi cisternae showing tubular interconnections and coated budding profiles.
Images were prepared from a Golgi enriched membrane fraction of Chinese hamster ovary cells (CHO). (A)
A bud protruding from a nonfenestrated edge of the central part of a cisterna. (B) A coated bud protruding
from the side of a tubular loop (arrow). (C) A fully formed coated vesicle with fibrous attachments to the cis-
terna. (D) A short tubule with a coated bud at the tip. Arrows point to tubules that seem to bend back and fuse
with the edge of the same cisterna that they emerge from, thus forming an irregular fenestration. Although not
formally identified in these preparations, current evidence indicates that the coats shown here are of the
COPI type. Bar, 0.5 mm. This figure was taken from Weidman et al. (1993) and reprinted with permission
from Cell # 1993.

TGN (Figs. 1 and 4B). Between and surround- likely form from the edges of the enclosing cis-
ing the cisternae a dense, ribosome-free protein ternae (Rambourg and Clermont 1986). These
network is present, the “Golgi matrix,” that are referred to as “wells” (Hermo et al. 1991).
might contain structural proteins (e.g., coiled Especially at the cis-to-medial side of the Golgi,
coil proteins) supporting the stack structure consecutive cisternae can align their wells,
(Franke et al. 1972; Cluett and Brown 1992; which then form indentations of the Golgi stack
Slusarewicz et al. 1994; Sinka et al. 2008). with a large activity of vesicle budding resulting
The central part of a given Golgi cisterna is in the presence of numerous vesicles (Ladinsky
usually quite narrow (10 – 20 nm), whereas the et al. 1999). The presence of fenestrae increases
edges, generally indicated as rims, are more the surface-to-volume ratio of the cisternae and
dilated. Especially at these dilated rims, the cis- introduces more curvature to the membranes.
ternae are perforated with membrane-bounded This might be important for the production
holes of up to 100 nm diameter (Fig. 5), which of vesicles and the segregation of proteins and
typically appear as gaps in 2D EM sections and lipids (Glick and Nakano 2009).
are called fenestrae. All cisternae are fenestrated, Within a given stack, connections between
but the fenestrae become smaller in the cis-to- heterologous cisternae can be formed (Fig. 1).
medial direction and then again increase in size These were first reported by Rambourg and col-
and number toward the trans-side of the Golgi leagues and are especially well visible in sperma-
(Ladinsky et al. 1999). Some fenestrae are of tids and Sertoli cells (Rambourg 1997). More
substantial size (.100 nm) and contain within recent studies have shown the presence of
their lumen a collection of small vesicles, which intercisternal tubular connections in additional

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 Golgi Architecture

cell types, including normal rat kidney (NRK) Golgi stacks are conserved throughout
and pancreatic b cells (Marsh et al. 2004; Trucco eukaryotic evolution, although some excep-
et al. 2004). The diameter of these tubules is tions are known, such as the budding yeast Sac-
about 20 nm (Marsh et al. 2004), which is of charomyces cerevisae (Rabouille and Kondylis
the same magnitude as the width of the cisternal 2007), in which the Golgi consists of individual
lumen. Although quantitation of these types of cisternae that are scattered throughout the cyto-
structures is not trivial, it seems that they are plasm. These cisternae occasionally associate
rare to absent in control cells with basal secre- with each other, but do not form a stack (Preuss
tory activity (Marsh et al. 2001a), but increase et al. 1992; Castillon et al. 2009; Papanikou and
in frequency in cells with high secretory activity, Glick 2009), yet can still be sub-divided into cis,
such as professional secreting cells (Rambourg medial, trans, and TGN (Brigance et al. 2000).
1997) or in cells which are experimentally trig- Lower animal cells and organisms (e.g., proto-
gered to protein synthesis (Marsh et al. 2004; zoa, the budding yeast Pichia pastoris, and the
Bouchet-Marquis et al. 2008; Vivero-Salmeron fruitfly Drosophila melanogaster) can form Golgi
et al. 2008). It has been shown that the arrival stacks, but these remain separate and are not
of cargo at the Golgi triggers the recruitment interconnected by tubules (Prydz et al. 2008;
of Group IVA Ca(2þ)-dependent, cytosolic Kondylis and Rabouille 2009). In D. melano-
PLA(2) to Golgi membranes, which induces for- gaster the Golgi stacks are typically found in
mation of the intercisternal tubules (San Pietro close association with ERES, forming units des-
et al. 2009). Thus far, such connections have ignated tER-Golgi units. Strikingly, some cells at
only been seen in mammalian cells. Their pos- specific stages of D. melanogaster development
sible function in intraGolgi transport is dis- do not show a Golgi stack, but instead clusters
cussed in Glick and Luini 2011. of vesicles and tubules. Secretion by these cells
The Golgi stack can show multiple sites of occurs with high efficiency (Kondylis and
close contact with the ER. ER membranes can Rabouille 2009). Finally, it was found that
flatten out to cisternae that closely follow and eukaryotic lineages lacking a morphologically
partially enwrap a trans- or the trans-most cis- identifiable Golgi do contain conserved Golgi
terna. These flattened ER cisternae lack ribo- proteins. This suggests that the Golgi can be
somes at the side facing the Golgi. Examples of altered beyond recognition, but that there exist
this type of interaction were first described by no “Golgi-lacking” eukaryotes (Dacks et al.
Novikoff and colleagues (Novikoff et al. 1971) 2003).
and since then were reported in various cell types
and by different EM approaches (Hand and
THE NONCOMPACT ZONE OF THE GOLGI
Oliver 1977; Pavelka and Ellinger 1983; Craig
and Staehelin 1988; Thorne-Tjomsland et al. From the fenestrated, peripheral regions of
1991; Marsh et al. 2001a; Meiblitzer-Ruppitsch the cisternae of the Golgi stack, lateral networks
et al. 2008). It is believed that these connections of 30 nm diameter tubules emerge. Some of
might facilitate protein and lipid exchange be- these tubular membranes bend back to fuse
tween membranes and/or are important for with the same cisterna that they emerge from,
maintaining structure (Levine and Rabouille forming another fenestration (Fig. 5, arrows).
2005; Hanada et al. 2007; Peretti et al. 2008; Glick Other tubules emanating from cis- and medial-
and Nakano 2009; Rocha et al. 2009). By 3D-elec- cisternae project backward to the VTCs (Fig. 1)
tron tomography, a second type of ER-Golgi (Rambourg 1997; Ladinsky et al. 1999; Glick
association was visualized consisting of an ER and Nakano 2009). Many tubules, however,
cisterna almost entirely devoid of ribosomes extend laterally, sometimes over a distance of
that traversed the Golgi stack through consecu- several micrometers, and fuse with tubules
tively aligned openings in the cisternae (Marsh from adjacent Golgi stacks, forming the tubular
et al. 2001a). The functional significance of this network that bridges adjacent stacks (Figs. 1
observation still needs to be established. and 5). These tubular networks are classically

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J. Klumperman

referred to as the noncompact zones of the coat. In standard EM sections, COPI and COPII
Golgi. The tubules can connect cisternae lo- coats cannot be distinguished. However, by
cated at the same positions in the respective immuno-labeling the coats on the rims of the
stacks, but also cisternae located at different lev- Golgi cisternae as well as on the Golgi associated
els (Rambourg 1997). vesicles were identified as the COPI type,
Volume measurements in insulin producing the same coat as found on VTC membranes
b cells of mice gave an estimated volume of 3.7 – (Oprins et al. 1993; Griffiths et al. 1995; Orci
5.8 mm3 for the total volume of the Golgi, of et al. 1997; Martinez-Menarguez et al. 2001;
which the Golgi stack comprised 3.1 – 3.6 mm3 Rabouille and Klumperman 2005). Many
(Noske et al. 2008). Thus, the noncompact COPI vesicles are tethered to the Golgi cisternae
zone of the Golgi substantially contributes to via long, rod-like proteins (Orci et al. 1998;
total Golgi volume. Recent studies indicate Marsh et al. 2001a), which might represent
that the formation of a Golgi ribbon is particu- members of the golgin protein family (Goud
larly important for protein glycosylation. The and Gleeson 2010).
Golgi ReAssembly Stacking Proteins GRASP65 COPI-coated membrane buds can form at
and GRASP55 function in the formation and/ the central, nonfenestrated area of a cisterna,
or maintenance of the tubules connecting the but are much more frequently seen at the fenes-
Golgi stacks, presumably by forming protein trated rims, in which they form directly on the
tethers between adjacent membranes (Barr cisternal membrane or at the tips of the tubules
et al. 1998; Shorter et al. 1999; Rabouille and that emanate from these regions (Weidman
Kondylis 2007; Feinstein and Linstedt 2008; et al. 1993). The majority of the buds associated
Vinke et al. 2011). Depletion of GRASP65 with Golgi cisternae are coated (Ladinsky et al.
and/or the “golgin” protein GM130 (Gilling- 1999). The highest number of COPI-coated
ham and Munro 2003; Barinaga-Rementeria buds is found on the cis-cisternae, with declin-
Ramirez and Lowe 2009) (for further details, ing numbers toward the trans-side and TGN
see Munro 2011) disturbs the Golgi ribbon. (Oprins et al. 1993; Ladinsky et al. 1999).
This results in the redistribution of Golgi The role of COPI vesicles in intraGolgi
enzymes over the stacks and affects proper transport is a topic of intense investigations
protein glycosylation, but does not cause a and debate. It is now generally accepted that
block in secretion (Puthenveedu et al. 2006; COPI coated vesicles mediate retrograde trans-
Marra et al. 2007b). It remains to be established, port of Golgi resident enzymes from maturing
however, whether GM130 acts directly in cisternae throughout the Golgi stack and of
homotypic fusion of neighboring cisternae ER-resident proteins to the ER (Emr et al.
(Puthenveedu et al. 2006) or mediates the teth- 2009). In addition, a subpopulation of COPI
ering of ER-derived vesicles with the cis-Golgi coated vesicles might be involved in antero-
(Marra et al. 2007a). Interestingly, unlinking grade transport of cargo through the Golgi
the Golgi ribbon is part of a putative G2/M stack (Orci et al. 1997; Malsam et al. 2005).
checkpoint (Sutterlin et al. 2002; Yoshimura The small size of the COPI vesicles and the dis-
et al. 2005; Rabouille and Kondylis 2007). tinct possibility that morphologically identical
COPI vesicles represent a mixed population
with regard to cargo and directionality, ham-
COPI COATS IN THE GOLGI STACK
pers their functional characterization. To fur-
The Golgi area contains numerous 60 – 100 nm ther address their role in Golgi transport, a
vesicles, especially concentrated in the Golgi distinction between distinct COPI vesicle sub-
wells and at the Golgi rims (Fig. 2, arrows). populations is required. A first study address-
Depending on the cell type and cellular activity, ing this point indeed showed that different
the number of these vesicles can add up to subtypes of COPI vesicles show a differential
more than 2000 per Golgi region (Marsh et al. distribution relative to the Golgi stack (Moel-
2001a). Many of these vesicles bear a COP leken et al. 2007).

10 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005181

 Golgi Architecture

THE TRANS-FACE OF THE GOLGI In ultrathin 2D-EM sections of cells with

a well-developed TGN, such as the human
The TGN is the main site of sorting of proteins
hepatoma HepG2 cells, the tubular TGN has a
and lipids for postGolgi destinations (Griffiths
striking and distinctive morphology, being a
and Simons 1986; Mellman and Simons 1992;
collection of branched tubules with many bud-
Traub and Kornfeld 1997; De Matteis and Luini
ding profiles and associated vesicles (Fig. 4B).
2008). The anterograde exit routes from the TGN
However, this morphology is strongly depend-
are to the apical plasma membrane, basolateral
ent on the cell type. In some cells, such as secre-
plasma membrane, recycling endosomes, early
tory cells or cultured NRK cells, the tubular
endosomes, late endosomes, and specialized
TGN aligns with only part of the Golgi ribbon
compartments, such as secretory granules, re-
or can even be completely absent (Rambourg
viewed by De Matteis and Luini (2008). In addi-
et al. 1979; Ladinsky et al. 1994; Clermont
tion, retrograde transport from the TGN to the
et al. 1995). In addition, the TGN undergoes
Golgi stack occurs (Sandvig et al. 2004; Johannes
dynamic changes in size and structure depend-
and Popoff 2008). For each destination a distinct
ing on the level of protein synthesis (Hand and
type of carrier might be used (Traub and Korn-
Oliver 1984; Griffiths et al. 1989).
feld 1997), but it still remains to be established
The morphological hallmark of the trans-
how many types of TGN exits there are.
most/TGN cisterna, which distinguishes it
from all other Golgi cisternae, is the presence
of clathrin (Pearse and Robinson 1990). Similar
TGN Architecture
to COP coats, clathrin deposits as an electron-
Morphologically, the TGN is defined as a tubu- dense layer on the cytoplasmic leaflets of mem-
lar, anastomosing (meaning branching, reticu- branes. The clathrin coat displays a typical spiky
lating) compartment at the trans-side of the pattern and is thicker than the COP coat (circa
Golgi stack that is continuous with the trans- 18 nm versus 10 nm), which makes it morpho-
most Golgi cisterna (Fig. 1) (Griffiths and logically distinct from COP coats and recogniz-
Simons 1986; Rambourg and Clermont 1990; able without the need for immuno-labeling
Geuze and Morre 1991). Hence, the TGN con- (Fig. 2) (Orci et al. 1984; Heuser and Kirchhau-
sists of a tubular and a cisternal part, with the sen 1985; Kirchhausen et al. 1986; Oprins et al.
latter being the trans-most cisterna of the Golgi 1993; Ladinsky et al. 1994). Clathrin can coat rel-
stack. The conversion of the cisternal mem- atively long distances of the cisternal part of the
brane into tubules is dependent on both pro- TGN membrane, which then is often curved
tein- and lipid-based mechanisms (De Matteis away from the stack. In addition, clathrin is as-
and Luini 2008). In addition to the trans-most sociated with the TGN tubules, in which it de-
cisterna, the penultimate trans-cisterna can also forms the membranes into clathrin coated buds
project tubules into the trans-region (Fig. 1), (Ladinsky et al. 2002; Mogelsvang et al. 2004).
which in 2D sections contributes to the overall These buds are wider than COP-coated buds
membrane complexity of the TGN area (Ram- and have an average diameter of circa 100 nm
bourg et al. 1979; Marsh and Howell 2002; (Mogelsvang et al. 2004; Peden et al. 2004). Nota-
Mogelsvang et al. 2004). The cisternal parts of bly, in addition to clathrin the TGN can also dis-
the two trans-cisternae are sparsely fenestrated play COPI-coated buds, albeit with much lower
and often only partially aligned with the pre- frequency (Oprins et al. 1993; Griffiths et al.
vious cisterna, as if they are detaching, or peel- 1995; Martinez-Menarguez et al. 1999).
ing off, from the Golgi stack (Rambourg et al.
1979; Geuze and Morre 1991). Where these
TGN Exits
trans-cisternae lose alignment with the stack,
they form the anastomosing tubules (Griffiths The clathrin-coated TGN buds give rise to
and Simons 1986; Clermont et al. 1995; Ram- clathrin-coated vesicles that transport mannose
bourg 1997). 6-phosphate tagged lysosomal enzymes bound

Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005181 11

J. Klumperman

to mannose 6-phosphate receptors (MPRs) to membranes that could contain branches and
endosomes. Clathrin-coated carriers are the fenestrations (Polishchuk and Mironov 2004).
best-characterized exit mechanism for antero- However, since there are no distinguishing struc-
grade transport from the TGN. After delivery tural features that specify these carriers when
of their cargo to the endosomal system, forming at the TGN, the ultrastructural details
the MPRs cycle back to the TGN for a new of this TGN exit have remained elusive.
round of transport (Kornfeld and Mellman In professional secretory cells, that is, those
1989; Pearse and Robinson 1990; van Meel possessing a regulated secretory pathway, the
and Klumperman 2008; Braulke and Bonifacino major TGN exit is to secretory granules (Kelly
2009). Interestingly, cells containing an exten- 1985; Huttner and Tooze 1989; Arvan and
sive lysosomal system in general show extensive Castle 1998). Secretory granules can be of sig-
tubulation of the TGN membranes (Clermont nificant size—up to several hundreds of nano-
et al. 1995; Rambourg 1997), which might meters—and accumulate in the cytoplasm
reflect the well-developed MPR recycling path- until they are triggered to fuse with the plasma.
way in these cells. Other types of membrane- The forming secretory granules—indicated as
bounded carriers also travel in both anterograde condensing vacuoles (CV)—are in most cells
and retrograde directions between the TGN and only seen at the TGN and, with clathrin, are
distinct endosomal intermediates (see Pfeffer morphological hallmarks to determine Golgi
2011). Hence, the membrane complexity of polarity (Fig. 1). However, in some cells or after
the TGN is determined by both biosynthetic strong stimuli, CVs can also be seen in one or
traffic coming from the Golgi stack and incom- more trans-Golgi cisternae (Rambourg et al.
ing traffic from the endocytic system (Farquhar 1984; Rambourg 1997; Slot et al. 1997; Arvan
and Palade 1981; Kornfeld and Mellman 1989; and Castle 1998). These, and other, observa-
Vetterlein et al. 2002). The cargo and destina- tions have raised the question as to whether
tions of TGN derived COPI-coated vesicles exit from the Golgi might also occur from ear-
have not been especially studied, but they likely lier cisternae and not be exclusively confined
represent a retrograde pathway (Cosson and to the TGN (for further discussion see below)
Letourneur 1994; Martinez-Menarguez et al. (Rambourg and Clermont 1990).
2001).
Proteins lacking a specific sorting signal
TGN Sorting
are by default packaged into vesicles of the
constitutive pathway to the plasma membrane There are currently two distinct models to
(Mellman and Simons 1992; Bossard 2007; De explain protein sorting in the TGN. The preva-
Matteis and Luini 2008). Moreover, in polarized lent model is that all proteins that travel through
(e.g., epithelial or neuronal) cells additional the Golgi stack enter the TGN from which
routes emerge from the TGN to target proteins they are sorted to their distinct destinations.
specifically to the apical (or axonal) versus However, based on the observations that (i)
basolateral (or dendritic) plasma membranes both the trans-most and the penultimate trans-
(Bennett et al. 1988; Dotti and Simons 1990; cisternae can project tubules into the TGN area
Wandinger-Ness et al. 1990). Polischuk and (Marsh et al. 2001a; Marsh et al. 2001b; Mogels-
colleagues have used a CLEM approach to mor- vang et al. 2004), (ii) that not all TGNs display the
phologically define the carriers involved in the tubular compartment and that (iii) induction of
constitutive transport of exogenously expressed a 208C block, hampering TGN exit, resulted in
vesicular stomatitis virus G (VSV-G) to the the swelling of the three last trans-Golgi cisternae
plasma membrane of nonpolarized cells. By (Ladinsky et al. 2002) it was postulated that
live cell imaging these carriers were found to distinct trans-cisternae might receive distinct
detach from tubular TGN membranes (see sets of cargoes that exit the Golgi sequentially
Malhotra and Campelo 2010) and by CLEM, (Ladinsky et al. 1994; Ladinsky et al. 1999; Ladin-
they were identified as noncoated, pleiomorphic sky et al. 2002; Mogelsvang et al. 2004). Thus, this

12 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005181

 Golgi Architecture

second model proposes that multiple trans-Golgi Another prediction of the alternative model
cisternae each form functionally distinct types for TGN sorting is that the penultimate trans
of exit compartments, as opposed to the original cisterna is consumed into the vesicles that
model that one membrane compartment (the mediate constitutive transport to the plasma
TGN), facilitates the sorting of mixed cargo types membrane (Mogelsvang et al. 2004). This is a
to multiple destinations. difficult point to prove since, as discussed
The second model proposes that proteins above, constitutive vesicles do not have distin-
destined for the endo-lysosomal pathways guishing structural features when forming at
would exit the Golgi from the clathrin-coated the TGN and, once formed, travel rapidly away
trans-most/TGN cisterna, whereas proteins from the Golgi. Fluorescence measurements in
destined for the constitutive pathway would exit live cells, however, have indicated that antero-
from the preceding trans-cisternae (Mogelsvang grade moving cargo might exit the Golgi stack
et al. 2004). A key question to distinguish be- at the level of multiple cisternae (Patterson
tween the two models is therefore how distinct et al. 2008), although it is not clear how this
cargoes distribute over the distinct trans-cister- relates to the fact that most vesicles surrounding
nae and TGN. There are several observations in the Golgi are COPI-coated. In the Golgi region
the literature indicating that the trans-most/ of insulin producing HIT-T15 cells the presence
TGN membrane can contain mixed cargo. For of noncoated vesicles was described (Mogels-
example, CVs in the TGN of professional secre- vang et al. 2004), but it cannot be excluded
tory cells can display clathrin- and COPI-coated that these represent uncoated COPI vesicles
buds (Fig. 1) (Orci et al. 1984; Martinez-Menar- and their cargo has remained unidentified.
guez et al. 1999), indicating the presence of Thus, the prevalent evidence is in favor of
three types of cargo (secretory, lysosomal, retro- the idea that the trans-Golgi/TGN cisternae is
grade) within the same membrane domain. the main sorting station of the Golgi, contain-
The actual presence of lysosomal enzymes in ing mixed cargo and showing exit sites to dif-
CVs was shown by immunoEM (Kuliawat et al. ferent destinations. However, the presence of
1997; Klumperman et al. 1998a). A second exam- multiple cargo types and exits from the TGN
ple is provided by polarized cells, in which two does not exclude the possibility that a subset
types of clathrin-coated vesicles emerge from of transport vesicles detaches at an earlier stage
the TGN. One of these, containing the m1B adap- during passage through the Golgi stack.
tin isoform of the AP-1 complex (Ohno et al.
1999), targets VSV-G to the basolateral mem-
VARIATIONS ON A THEME
brane (Folsch et al. 2003). Since clathrin only as-
sociates with the trans-most/TGN cisterna this Within the general concept outlined above, the
finding implies that VSV-G enters the clathrin- architecture of the Golgi and its associated com-
coated TGN membrane. This was confirmed by partments is subject to many variables. Golgi
immunoEM showing the presence of VSV-G structure varies by cell type. For example, in
in all cisternae (Griffiths et al. 1985; Griffiths neurons and Sertoli cells, the Golgi covers a large
et al. 1989). Other examples of mixed cargoes area of the cytoplasm, whereas in, for example,
within the same trans-most/TGN cisterna are: leukocytes or plasma cells the Golgi is compact
secretory lipoprotein particles and lysosomal and spherical (Rambourg 1997). Within a given
enzymes (Farquhar et al. 1974; Farquhar and cell type, the Golgi volume depends on the level
Palade 1981); endocytosed transferrin and the of protein synthesis. Inhibition of ER to Golgi
constitutive secreted protein albumin (Stoorvo- traffic can lead to the disappearance of the Golgi
gel et al. 1988); albumin, MPR and lysosomal (Lee and Linstedt 1999; Glick 2000; Morin-
enzymes (Geuze et al. 1985); the recycling asia- Ganet et al. 2000; Prescott et al. 2001), whereas
loglycoprotein receptor and MPRs (Geuze et al. an increase in synthesis can lead to increased
1987); the constitutive secreted protein procol- Golgi volume (Clermont et al. 1993; Noske
lagen and clathrin (Bonfanti et al. 1998). et al. 2008). The Golgi adapts to these changes

Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005181 13

J. Klumperman

by Golgi-based signaling systems (Farhan and Bannykh SI, Nishimura N, Balch WE. 1998. Getting into the
Golgi. Trends Cell Biol 8: 21–25.
Rabouille 2011), for example, by monitoring
Bannykh SI, Rowe T, Balch WE. 1996. The organization of
protein chaperones that escape the ER. In the endoplasmic reticulum export complexes. J Cell Biol
Golgi, these proteins bind to the KDEL recep- 135: 19–35.
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Golgi-based signaling cascade that activates in- the ER: what’s the ticket out?. Trends in cell biology 13:
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Barlowe C, Orci L, Yeung T, Hosobuchi M, Hamamoto S,
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Finally yet importantly, the Golgi undergoes
Barr FA, Nakamura N, Warren G. 1998. Mapping the inter-
profound remodeling during mitosis and apop- action between GRASP65 and GM130, components of a
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nae. EMBO J 17: 3258– 3268.
Beams HW, Kessel RG. 1968. The Golgi apparatus: structure
CONCLUDING REMARKS and function. Int Rev Cytol 23: 209–276.
Bennett MK, Wandinger-Ness A, Simons K. 1988. Release of
Extensive ultrastructural research has generated putative exocytic transport vesicles from perforated
a general outline of Golgi architecture in mam- MDCK cells. EMBO J 7: 4075– 4085.
Bonfanti L, Mironov AA Jr, Martinez-Menarguez JA, Mar-
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tella O, Fusella A, Baldassarre M, Buccione R, Geuze
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involved in Golgi structure and function should evidence for cisternal maturation. Cell 95: 993 –1003.
Bossard C, Bresson D, Polishchuk RS, Malhotra V. 2007.
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Dimeric PKD regulates membrane fission to form trans-
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ACKNOWLEDGMENTS the Golgi complex: staying put and moving through.
Semin Cell Dev Biol 20: 784–792.
The author thanks Catherine Rabouille, Viola Castillon GA, Watanabe R, Taylor M, Schwabe TM, Riezman
Oorschot, and Maaike Pols for critical reading H. 2009. Concentration of GPI-anchored proteins upon
ER exit in yeast. Traffic 10: 186–200.
and input on the manuscript and Rene Scriwa-
Clermont Y, Rambourg A, Hermo L. 1994. Connections
nek and Marc van Peski for assistance with the between the various elements of the cis- and mid-
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