Models for Golgi Traffic: A Critical Assessment

Models for Golgi Traffic: A Critical Assessment

Benjamin S. Glick1 and Alberto Luini2

1Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago,Illinois 60637

2Telethon Institute of Genetics and Medicine, 80131 Naples, Italy

Correspondence: [email protected]; [email protected]

Avariety of secretory cargoes move through the Golgi, but the pathways and mechanisms ofthis traffic are still being debated. Here, we evaluate the strengths and weaknesses of fivecurrent models for Golgi traffic: (1) anterograde vesicular transport between stable compart-ments, (2) cisternal progression/maturation, (3) cisternal progression/maturation withheterotypic tubular transport, (4) rapid partitioning in a mixed Golgi, and (5) stable compart-ments as cisternal progenitors. Each model is assessed for its ability to explain a set of keyobservations encompassing multiple cell types. No single model can easily explain all ofthe observations from diverse organisms. However, we propose that cisternal progression/maturation is the best candidate for a conserved core mechanism of Golgi traffic, and thatsome cells elaborate this core mechanism by means of heterotypic tubular transportbetween cisternae.

Golgi traffic is an ancient process (Kluteet al. 2011). Certain core mechanisms are

likely to be conserved in most or all eukaryotes,but these core mechanisms have undoubtedlybeen enhanced or modified during evolution.Among the options available in the endomem-brane system are vesicular transport, tubularextensions and connections, homotypic fusionof compartments, and compartment matura-tion (Schnepf 1993; Rothman 1994; Beckeret al. 1995; Schekman and Orci 1996; Bannykhand Balch 1997; Glick et al. 1997; Mironovet al. 1997; Marsh et al. 2004; Trucco et al.2004; Rink et al. 2005). A unifying model shouldattempt to describe the core mechanisms ofGolgi traffic while accounting for species-spe-cific variations.

It is hardly an exaggeration to state thatthere are as many different models for Golgitraffic as there are Golgi researchers. This lackof consensus reflects the complexity and sub-tlety of the topic. We believe that a completemodel for Golgi traffic should explain the fol-lowing observations:

1. In most eukaryotes, distinct Golgi com-partments can be identified by morpholog-ical and biochemical criteria. The numberof Golgi compartments is subject to debate(Mellman and Simons 1992), but a typicaldescription includes cis, medial, and transcisternae plus the trans-Golgi network(TGN) (Dunphy and Rothman 1985; Far-quhar 1985). These compartments differ

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in their structure, cytochemical-stainingproperties, composition of resident Golgienzymes, and ability to bud COPI- or cla-thrin-coated vesicles (Farquhar and Palade1981; Kleene and Berger 1993; Rabouilleet al. 1995; Staehelin and Kang 2008; Nils-son et al. 2009).

2. Glycosylation enzymes in the Golgi showa polarized distribution that reflects thesequence of oligosaccharide processing re-actions. In species ranging from mammalsto fungi to plants, early-acting glyco-sylation enzymes are concentrated in cis-cisternae, whereas late-acting glycosylationenzymes are concentrated in trans-cisternae(Kleene and Berger 1993; Rabouille et al.1995; Nilsson et al. 2009; Schoberer et al.2010).

3. Secretory cargoes can be observed to moveacross mammalian Golgi stacks in thecis-to-trans direction. Such “cargo waves”have been seen for both small secretorycargo proteins and large macromolecularaggregates (Bergmann and Singer 1983;Bonfanti et al. 1998; Mironov et al. 2001;Trucco et al. 2004).

4. Golgi structure varies between organisms.Golgi cisternae are organized as individ-ual cisternae in Saccharomyces cerevisiae(Preuss et al. 1992), as single stacks in manyplants and unicellular organisms (Melko-nian et al. 1991; Yelinek et al. 2009), as pairsof stacks in Drosophila (Kondylis andRabouille 2009), or as a ribbon of laterallylinked stacks in mammalian cells (Ram-bourg and Clermont 1990). In microspori-dia, the Golgi appears to be a membranenetwork rather than a collection of discretecisternae (Beznoussenko et al. 2007).

5. COPI vesicles appear to be associatedwith Golgi structures in most eukaryotes.Electron microscopy and cell-free reconsti-tution identified COPI vesicles as intra-Golgi carriers (Rothman 1994). As judgedby electron tomography, a mammalianGolgi stack may be surrounded by morethan a thousand COPI vesicles (Ladinsky

et al. 1999). Presumptive COPI vesiclesare also abundantly visible around algalGolgi stacks (Farquhar and Palade 1981;Staehelin and Kang 2008). Although peri-Golgi vesicles are less evident in other celltypes, COPI is broadly conserved (Dackset al. 2009).

6. COPI vesicles function in retrograde traffic.Strong biochemical and genetic data impli-cate COPI vesicles in recycling of proteinsfrom the Golgi to the ER (Letourneur et al.1994; Pelham 1994; Gaynor et al. 1998).

7. Large secretory cargoes can traverse theGolgi. In diverse cell types, secretory car-goes much larger than COPI vesicles aretransported through Golgi stacks. Thebest-characterized examples are cell surfacescales in algae (Brown 1977; Melkonianet al. 1991) and procollagen aggregates inmammalian fibroblasts (Leblond 1989;Bonfanti et al. 1998; Mironov et al. 2001;Trucco et al. 2004).

8. Morphological data suggest that Golgicisternae form at the cis-face of the stack,and peel off and fragment at the trans-face.Electron micrographs of cell types rangingfrom plants to fungi to mammals suggestthat cisternae assemble at the cis-face of aGolgi stack, and separate from the stackat the trans-face while undergoing fission(Morre and Ovtracht 1977; Ladinsky et al.1999; Mogelsvang et al. 2003; Staehelinand Kang 2008).

9. Resident Golgi proteins can move rapidlywithin and between compartments. Golgiproteins show overlapping distributionsacross multiple cisternae, and their concen-trations in particular compartments evi-dently reflect the dynamics of membranetraffic rather than static localization mech-anisms (Hoe et al. 1995; Rabouille et al.1995; Harris and Waters 1996).

10. Golgi compartments in Saccharomyces cer-evisiae are transient. The individual Golgicisternae in S. cerevisiae can be resolvedby fluorescence microscopy (Wooding and

B.S. Glick and A. Luini

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Pelham 1998). Video imaging of S. cerevi-siae cells revealed that over a time-courseof several minutes, Golgi compartmentsexchange their early resident proteins forlate resident proteins (Losev et al. 2006;Matsuura-Tokita et al. 2006).

11. In mammalian cells, Golgi cisternae aresometimes linked by heterotypic tubularmembrane connections within a single stack.These tubular connections are visible by elec-tron tomography in actively secreting cells(Marsh et al. 2004; Trucco et al. 2004; SanPietro et al. 2009). Treatments that interferewith tubulation inhibit membrane traffic(San Pietro et al. 2009; Bechler et al. 2010).

12. Small soluble secretory cargoes can traversethe mammalian Golgi stack very rapidly.Whereas cargoes such as VSV-G and pro-collagen require �15 minutes to traverse aGolgi stack, some cargoes such as albumincross the entire stack in under two minutes(A Luini et al. in prep.).

13. In mammalian cells, secretory cargoes exitthe Golgi region with exponential kinet-ics. When fluorescent secretory cargo mole-cules were tracked over time, exit from theGolgi region followed first-order kinetics,suggesting that the fluorescent moleculeswere present in a long-lived and well-mixedcompartment (Patterson et al. 2008).

In the following sections, we evaluate fivecurrent models for their ability to explain theseobservations.

MODEL 1: ANTEROGRADE VESICULARTRANSPORT BETWEEN STABLECOMPARTMENTS

The vesicular transport model (Fig. 1) waswidely accepted from the early 1980s until thelate 1990s. The Golgi is viewed as a set of stablecompartments operating in tandem (Farquharand Palade 1981; Rothman 1981; Dunphy andRothman 1985; Farquhar 1985). Each compart-ment would contain a unique set of residentGolgi proteins, including glycosylation enzymesthat operate in assembly line fashion to process

secretory cargoes (Kleene and Berger 1993;Rabouille et al. 1995; Nilsson et al. 2009). Anewly synthesized secretory cargo would bedelivered to the cis-Golgi in COPII-coatedvesicles, and would then move from one Golgicompartment to the next in COPI-coatedvesicles (Rothman and Wieland 1996). ResidentGolgi proteins are assumed to be localized tospecific compartments by exclusion from an-terograde COPI vesicles. Updated versions ofthe stable compartments model propose thatCOPI vesicles move bidirectionally, with an-terograde COPI vesicles carrying secretory car-goes forward whereas retrograde COPI vesiclesrecycle trafficking components (Orci et al.2000b; Pelham and Rothman 2000).

Strengths

† This model can easily explain the existence ofdistinct Golgi compartments, the polarizeddistribution of Golgi glycosylation enzymes,and the existence of secretory cargo waves.Moreover, this model can accommodatemuch of the variability in Golgi structure,and it provides functions for COPI vesiclesas bidirectional carriers. Because of thesefactors, the stable compartments concept re-mains appealing.

† Some studies have identified secretory cargoesin COPIvesicles. Immunoelectron microscopyand biochemical analysis provided evidencethat COPI vesicles contain several secretorycargoes, including VSV-G protein, proinsulin,and the polymeric immunoglobulin A recep-tor (Ostermann et al. 1993; Orci et al. 1997;Malsam et al. 2005).

† COPI vesicles seem to come in two types,which could represent anterograde versusretrograde vesicles. Studies of both mam-malian and plant cells have revealed the exis-tence of two classes of COPI vesicles thatdiffer in morphological appearance and pro-tein composition (Orci et al. 1997; Malsamet al. 2005; Moelleken et al. 2007; Staehelinand Kang 2008).

† Rapidly “percolating” vesicles could explainthe fast intra-Golgi traffic of small secretory

Models for Golgi Traffic

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cargoes, as well as the exponential kinetics ofsecretory cargo exit from the Golgi region. Itis possible that secretory cargoes move bidi-rectionally across the stack by rapid COPIvesicle-mediated transport (Orci et al.2000b; Pelham and Rothman 2000). If bidi-rectional transport between cisternae is fastrelative to exit from the Golgi, the exitkinetics should be exponential.

Weaknesses

† The abundance of COPI vesicles variesdramatically between organisms and evenwithin a given cell type. COPI vesicles aroundthe mammalian Golgi actually seem to be less

abundant during active traffic (Clermontet al. 1993; Rambourg et al. 1993).

† A number of studies have not detected smallsecretory cargoes in COPI vesicles. Variousinvestigators have analyzed the compositionof COPI vesicles using immunoelectronmicroscopy or proteomics, and have con-cluded that secretory cargoes such as VSV-G protein and albumin are depleted ratherthan enriched in these vesicles (Dahan et al.1994; Martinez-Menarguez et al. 2001; Gil-christ et al. 2006).

† The evidence for anterograde COPI vesicletraffic is inconclusive, and the two types ofCOPI vesicles could both be retrograde

TGN

IC

ER

TGN proteinstrans proteinsMedial proteinscis proteins

Small cargo

Golgi

trans

medial

cis

PM

Figure 1. Anterograde vesicular transport between stable compartments. Secretory cargoes travel from the ER tothe intermediate compartment (IC) and cis-Golgi in dissociative carriers. Golgi compartments are stable andbiochemically distinct. Secretory cargoes move across the stack by means of COPI vesicles that bud from onecompartment and fuse with the next, whereas resident Golgi proteins stay in place by being excluded from bud-ding vesicles. This model does not provide a mechanism for transporting secretory cargoes that are too large tofit within COPI vesicles.





carriers. Morphological analysis of plant andalgal cells suggested that one type of COPIvesicle functions in Golgi-to-ER retrogradetransport, whereas the second type is anintra-Golgi carrier that may recycle residentGolgi proteins (Staehelin and Kang 2008)(see Fig. 6B). A parsimonious interpretationof the data is that COPI vesicles act exclu-sively as retrograde carriers (Pelham 1994).

† Vesicular transport would need to be unreal-istically rapid and extensive to explain thefast intra-Golgi traffic of small secretory car-goes. Although bidirectional vesicular trans-port could theoretically explain how smallsecretory cargoes can sample the whole Golgiin a short time, calculations indicate thateach cisterna would need to produce hun-dreds of vesicles per second (A Luini et al.in prep.).

† This model cannot easily explain the trafficof large secretory cargoes, the fused Golginetwork in microsporidia, the apparent for-mation and peeling off of Golgi cisternae,the mobility of resident Golgi enzymesbetween compartments, the transient natureof yeast Golgi cisternae, or the existence ofheterotypic tubular connections between cis-ternae. In particular, the finding that largesecretory cargoes can transit through theGolgi has long served as an argument againstthe generality of the stable compartmentsmodel (Becker et al. 1995; Bonfanti et al.1998).

MODEL 2: CISTERNAL PROGRESSION/MATURATION

The cisternal progression/maturation model(Fig. 2) builds on the cisternal progression con-cept that was put forth by morphologists severaldecades ago (Grasse 1957; Morre and Ovtracht1977). Cisternae are viewed as transient carriers.Homotypic fusion of COPII vesicles or otherER-derived carriers (Bannykh and Balch 1997;Mironov et al. 2003) is proposed to nucleatethe formation of a new cis-cisterna, which grad-ually matures into a TGN cisterna, which inturn disintegrates into secretory vesicles and

other types of carriers. As the cisternae carrythe secretory cargoes forward (Bonfanti et al.1998), COPI vesicles would recycle residentGolgi proteins from older to younger cisternae(Glick and Malhotra 1998; Rabouille andKlumperman 2005). Differential recycling ef-ficiencies for different Golgi proteins couldexplain the biochemical polarity of the Golgi(Glick et al. 1997; Weiss and Nilsson 2000).It was recently postulated that the variousGolgi compartments represent discrete kineticstages of maturation, with the transition fromone stage to the next being regulated by RabGTPases (Glick and Nakano 2009).

Strengths

† This model can readily explain the existenceof distinct Golgi compartments, the po-larized distribution of Golgi glycosylationenzymes, the existence of secretory cargowaves, the transport of large secretory car-goes, the apparent formation and peelingoff of Golgi cisternae, the mobility of residentGolgi enzymes between compartments, andthe transient nature of yeast Golgi cisternae.Moreover, this model can accommodatemuch of the variability in Golgi structure,and it provides a function for COPI vesiclesas retrograde carriers. The idea that COPIvesicles recycle resident Golgi proteins re-solves many of the issues that led to thedownfall of the original cisternal progressionmodel (Glick and Malhotra 1998).

† Certain resident Golgi proteins have beenconvincingly identified as components ofCOPI vesicles, and some studies have identi-fied Golgi glycosylation enzymes in COPIvesicles. There is general agreement thatmammalian COPI vesicles contain theKDEL receptor (Orci et al. 1997; Aoe et al.1998), Golgi-localized SNARE proteins(Kweon et al. 2004; Volchuk et al. 2004),and the tethering protein giantin (Sonnich-sen et al. 1998). In some studies, residentGolgi glycosylation enzymes were also foundto be concentrated in COPI vesicles (Marti-nez-Menarguez et al. 2001; Malsam et al.2005; Gilchrist et al. 2006).





Weaknesses

† Several groups have reported that Golgi gly-cosylation enzymes are actually depleted inCOPI vesicles. Some immunoelectron mi-croscopy studies have not detected signifi-cant levels of Golgi glycosylation enzymesin COPI vesicles, contradicting a key predic-tion of the cisternal progression/maturationmodel (Orci et al. 2000a; Cosson et al. 2002;Kweon et al. 2004).

† This model cannot easily explain the fusedGolgi network in microsporidia, the exis-tence of heterotypic tubular connectionsbetween cisternae, the rapid intra-Golgi

traffic of small secretory cargoes, or the expo-nential kinetics of secretory cargo exit fromthe Golgi region. In a simple progression/maturation model, all secretory cargoesshould progress through the Golgi at thesame rate and should exit the Golgi with lin-ear kinetics. Recent studies have presentedevidence against both of these predictions(Patterson et al. 2008; A Luini et al., inprep.). To explain the exponential kineticsof secretory cargo exit, the cisternal progres-sion/maturation model would need to bemodified to include a long-lived TGN orpost-TGN compartment (Patterson et al.2008; Glick and Nakano 2009).

TGN

IC

ER


Small cargoLarge cargo

Golgi

trans

medial

cis

PM

Figure 2. Cisternal progression/maturation. Secretory cargoes exit the ER in dissociative carriers, which coalescewith one another and with COPI vesicles derived from the cis-Golgi to form the intermediate compartment,which coalesces in turn to form a new cis-cisterna. In subsequent rounds of COPI-mediated recycling, thenew cisterna matures by receiving medial and then trans-Golgi proteins from older cisternae while exportingcis and then medial-Golgi proteins to younger cisternae. Meanwhile, the cisterna progresses through the stack,carrying forward both small and large secretory cargoes. In the final stage of maturation, the cisterna is a TGNelement that breaks down into anterograde and retrograde transport carriers.





MODEL 3: CISTERNAL PROGRESSION/MATURATION WITH HETEROTYPICTUBULAR TRANSPORT

The cisternal progression/maturation modelcan be extended to incorporate tubular connec-tions between cisternae (Fig. 3). It is knownthat mammalian Golgi stacks are linked “hori-zontally” by homotypic tubular connectionsto form the Golgi ribbon (Rambourg andClermont 1990), and for many years, the ideahas been discussed that Golgi cisternae withina stack might also be linked “vertically” byheterotypic tubular connections (Mellmanand Simons 1992; Weidman 1995; Mironovet al. 1997). Recent electron tomography studieshave shown the presence of such heterotypictubular connections (Marsh et al. 2004; Truccoet al. 2004). Meanwhile, functional studies

have implicated enzymes of phospholipidmetabolism in the generation of Golgi-derivedmembrane tubules, and have indicated thattubules are important for anterograde and ret-rograde traffic in the ER-Golgi system (Weigertet al. 1999; Brown et al. 2003; San Pietro et al.2009; Schmidt and Brown 2009). Heterotypictubular connections are proposed to comple-ment cisternal progression/maturation by al-lowing either fast anterograde traffic of smallsecretory cargoes, or retrograde traffic of resi-dent Golgi proteins, or both (San Pietro et al.2009; A Luini et al. in prep.).

Strengths

† This model has all of the strengths of thecisternal progression/maturation model. Inaddition, it can explain the rapid intra-Golgi

TGN

IC

ER



Golgi

trans

medial

cis

PM

Figure 3. Cisternal progression/maturation with heterotypic tubular transport. This model is identical to thecisternal progression/maturation model, except that cisternae within a given stack are connected by tubular con-tinuities through which small secretory cargoes and resident Golgi proteins can diffuse. Tubular continuitiesmay also exist between heterotypic cisternae in adjacent stacks (not shown).





traffic of small secretory cargoes, and it pro-vides functions for heterotypic tubular con-nections. Narrow tubular connections mayprovide a “fast track” that allows small secre-tory cargoes to traverse the Golgi withoutrequiring extensive membrane transport.Moreover, these connections may allowGolgi glycosylation enzymes to recycle inde-pendently of COPI vesicles (San Pietro et al.2009).

† For small secretory cargoes, this model canexplain the exponential kinetics of exitfrom the Golgi region. If a protein can dif-fuse rapidly between cisternae, this proteinshould behave as if the Golgi were a singlewell-mixed compartment.

† The fused Golgi network in microsporidiacan be viewed as a variation of a verticallyconnected Golgi stack. Heterotypic tubularconnections may be so extensive in micro-sporidia that the Golgi is effectively a singlecompartment.

Weaknesses

† This model cannot easily explain the expo-nential kinetics of exit of the large secretorycargo procollagen from the Golgi region.Procollagen is too large to diffuse throughheterotypic tubular connections. Instead,procollagen seems to traverse Golgi stacksby cisternal progression, which should pro-duce linear kinetics of exit from the Golgiregion (Bonfanti et al. 1998; Patterson et al.2008).

† Heterotypic tubular connections betweenGolgi cisternae have not been convincinglydescribed in fungal and plant cells, and theprevalence of these connections in mamma-lian cells is still debated. Different groupsdisagree about whether heterotypic tubularconnections are common or rare in mamma-lian Golgi stacks (Martinez-Menarguez et al.2001; Marsh et al. 2004; Trucco et al. 2004;Vivero-Salmeron et al. 2008; Mavillard et al.2010). Moreover, such connections havenot yet been detected by tomographic analy-sis of fungal and plant cells (Mogelsvang et al.

2003; Staehelin and Kang 2008). Thesecaveats raise the possibility that heterotypictubular connections are a specialization ofcertain cell types or a response to overloadingthe secretory pathway.

† Questions remain about how Golgi compart-mentation can be maintained in the presenceof heterotypic membrane continuities. IfGolgi cisternae are connected vertically, un-known mechanisms must exist to preservegradients across the stack of resident Golgiprotein distribution, lipid composition,and pH.

MODEL 4: RAPID PARTITIONING IN AMIXED GOLGI

A recent paper proposed a dramatic revision oftraditional perspectives on the Golgi (Pattersonet al. 2008; Lippincott-Schwartz and Phair2010). According to the rapid partitioningmodel (Fig. 4), the Golgi operates as a singlecompartment that contains processing domainsand export domains. Secretory cargoes wouldarrive from the ER, partition between the twodomains of the Golgi, and then stochasticallyexit from every level of the Golgi to their finaldestinations. This model was inspired by thefinding that multiple secretory cargoes exitedthe Golgi region with exponential kinetics.The concept of distinct domains within theGolgi is based on fluorescence microscopydata suggesting that VSV-G protein, a trans-membrane secretory cargo, was partiallysegregated from Golgi glycosylation enzymes(Patterson et al. 2008).

Strengths

† This model can readily explain the transportof large secretory cargoes, the mobility of res-ident Golgi enzymes, the existence of hetero-typic tubular connections between cisternae,the rapid intra-Golgi traffic of small secretorycargoes, and the exponential kinetics of exitof both small and large secretory cargoesfrom the Golgi region. Notably, a numberof variations on the cisternal progression/maturation model were unable to explain





the observed exponential kinetics of secre-tory cargo exit (Patterson et al. 2008).

† The Golgi of microsporidia seems to be a sin-gle mixed compartment. This organism lacksobvious COPI vesicles, and evidently has asingle Golgi compartment between the ERand plasma membrane (Beznoussenko et al.2007).

Weaknesses

† This model cannot easily explain the exis-tence of discrete cisternae and distinctGolgi compartments in most eukaryotes,the polarized distribution of Golgi glyco-sylation enzymes, the existence of secretorycargo waves for procollagen, the apparent

formation and peeling off of Golgi cisternae,or the transient nature of yeast Golgi cister-nae. Moreover, this model provides no rolefor COPI vesicles. The assumption that secre-tory cargoes immediately sample the entireGolgi is troublesome, because Golgi enzymedistributions show a conserved cis-to-transpolarity that reflects the order of oligosac-charide processing reactions (Emr et al.2009). Another serious concern is thatalthough secretory cargo waves of VSV-Gprotein could be explained with a simulationinvolving diffusion and selective partition-ing (Patterson et al. 2008), this explanationdoes not apply to the secretory cargo wavesseen for the slowly diffusing procollagen(Bonfanti et al. 1998; Mironov et al. 2001;Trucco et al. 2004).

TGN

IC

ER



Gol

gi

trans

medial

cis

PM

Figure 4. Rapid partitioning in a mixed Golgi. As soon as secretory cargoes enter the Golgi, they equilibrateacross the stack via intercisternal continuities. Secretory cargoes partition dynamically between processingdomains, which contain resident Golgi proteins, and export domains. These various domains are establishedby segregation of different lipid species. Secretory cargoes can exit the Golgi at every level of the stack.





† This model goes well beyond the experimen-tal data. A general issue with the rapid parti-tioning model is that it invokes micron-scale“lipid raft” domains, yet lipid domains ofthis size have not been observed in cells (Eg-geling et al. 2009).

MODEL 5: STABLE COMPARTMENTS ASCISTERNAL PROGENITORS

The newest attempt to explain how the Golgiworks is the cisternal progenitor model (Fig. 5),although this model resembles earlier proposals(Griffiths 2000; Mironov et al. 2005). The Golgiis viewed as a set of stable compartments thatare segregated into domains defined by Rab

GTPases (Pfeffer 2010). This idea builds onstudies indicating that in endosomes, Rab pro-teins can establish distinct domains within amembrane (Sonnichsen et al. 2000) and candrive the biochemical transformation of a com-partment by a process known as “Rab conver-sion” (Rink et al. 2005; Nordmann et al. 2010;Poteryaev et al. 2010). Rab proteins can alsopromote the homotypic fusion of endosomes(Rink et al. 2005). By analogy, a domain in aGolgi cisterna is postulated to undergo Rabconversion followed by “homotypic” antero-grade fusion with a matching Rab domain in alater cisterna from an adjacent Golgi stack.Thus, secretory cargoes could move forwardthrough the Golgi by transferring back and

TGN

IC

ER



Gol

gi

trans

medial

cis

PM

Figure 5. Stable compartments as cisternal progenitors. Secretory cargoes travel from the ER to the intermediatecompartment and cis-Golgi in dissociative carriers. Golgi compartments are stable and biochemically distinct,but can segregate into domains by a Rab conversion process. A domain in a cis-cisterna undergoes Rab conver-sion and acquires medial character, resulting in a transient “homotypic” fusion with a medial cisterna in an adja-cent stack. Small and large secretory cargoes can move forward through the resulting connection. Similardomain fusion events in later compartments enable secretory cargoes to traverse the entire stack.





forth between adjacent stacks. Alternatively, aRab domain could pinch off from a cisterna tocreate a “megavesicle,” which would then fusewith a later cisterna from the same Golgi stack.The transfers of Rab domains are presumed tooperate in conjunction with COPI-mediatedvesicular transport (Pfeffer 2010).

Strengths

† This model can potentially explain the exis-tence of distinct Golgi compartments, thepolarized distribution of Golgi glycosyla-tion enzymes, the existence of secretorycargo waves, the transport of large secretorycargoes, the mobility of resident Golgienzymes, the existence of heterotypic tubularconnections between cisternae, the rapidintra-Golgi traffic of small secretory cargoes,and the fused Golgi network in microspori-dia. Because the cisternal progenitor modelencompasses a range of possible mecha-nisms, including heterotypic connectionsas well as traffic by conventional vesicles ormegavesicles, this model can be viewed asconsistent with multiple observations.

† Studies of mammalian endosomes and yeastsecretion supply precedents for the proposedmechanisms. Rab5 can promote homotypicfusion of early endosomes, and early endo-somes marked by Rab5 undergo conversioninto late endosomes marked by Rab7 (Rinket al. 2005; Nordmann et al. 2010; Poteryaevet al. 2010). In yeast, a Rab conversion mech-anism appears to operate during TGN-to-cell surface transport (Rivera-Molina andNovick 2009).

† This model predicts the possible existenceof megavesicle transport intermediates, andputative megavesicles were described in onestudy. Such megavesicles could transportlarge cargoes within a single Golgi stack (Vol-chuk et al. 2000).

Weaknesses

† This model cannot easily explain some ofthe variations in Golgi structure, the apparent

formation and peeling off of Golgi cisternae,or the transient nature of yeast Golgi cister-nae. Moreover, this model provides no spe-cific role for COPI vesicles. The cisternalprogenitor model is most appropriate foranimal cells, in which Golgi stacks can bearranged in adjacent pairs or in a laterallylinked ribbon (Rambourg and Clermont1990; Kondylis and Rabouille 2009). How-ever, individual Golgi stacks are found inplants, algae, and fungi (Melkonian et al.1991; Staehelin and Kang 2008; Yelineket al. 2009), making domain transfer betweenstacks improbable. In S. cerevisiae, many ofthe Golgi compartments mature as individ-ual structures without undergoing obviousfusion or fission (Losev et al. 2006; Mat-suura-Tokita et al. 2006).

† Megavesicles have not generally been ob-served as intra-Golgi carriers. Careful mor-phological studies of procollagen-secretingfibroblasts and scale-producing algae havevisualized the large secretory cargoes withincisternae, but not within megavesicle-typecarriers (Melkonian et al. 1991; Bonfantiet al. 1998; Trucco et al. 2004). A thin-sectionmicrograph interpreted as showing a dis-continuity in a mammalian Golgi cisterna(Pfeffer 2010) probably represented a perfo-ration (“well”) spanning multiple cisternae(Ladinsky et al. 1999; Staehelin and Kang2008).

† The lack of specificity of the cisternal progen-itor model poses a challenge for making test-able predictions. For example, it is unclearhow to predict the kinetics of secretory cargoexit from the Golgi region. The existence ofRab conversion in the Golgi has been pro-posed as a test of the cisternal progenitormodel (Pfeffer 2010), but Rab conversion isan equally plausible mechanism for cis-ternal maturation (Glick and Nakano 2009).Indeed, Rab conversion apparently underliesthe maturation of early endosomes into lateendosomes (Rink et al. 2005; Nordmannet al. 2010; Poteryaev et al. 2010), suggestingthat an analogous process could occur inthe Golgi.





CONCLUSIONS

The models described here differ in fundamen-tal ways, but they all offer insights into Golgitraffic. Emerging technologies will help usto distinguish between the various proposals(Rothman 2010). Meanwhile, we can offersome tentative conclusions.

A crucial point is that ideas about the Golgiare necessarily constrained by microscopy. Ourmodels must fit with what we see in different celltypes. By this criterion, cisternal progression/maturation is still the best candidate for abroadly conserved mechanism that operates inmost eukaryotes. This model provides themost compelling explanation for key findingsfrom mammalian, fungal, plant, and protistcells. An illustration is given in Figure 6, whichreproduces previously published images ofGolgi stacks in the alga Scherffelia dubia. Scale-forming algae can serve as a “reality check” formodels of Golgi traffic (Becker et al. 1995).Figure 6A shows a thin-section electron micro-graph of S. dubia (Perasso et al. 2000). TwoGolgi stacks are visible, but they are separatedby the nucleus, strongly suggesting that eachstack operates as an independent traffickingdevice. Figure 6B shows a tomographic slicefrom a 3D reconstruction of a rapidly frozenS. dubia cell. The excellent preservation revealsthat Golgi cisternae are separate compartmentsthat are relatively smooth and uninterrupted.This Golgi stack is surrounded by vesicles, pre-sumably of the COPI variety, but peri-Golgivesicles in algae do not contain scales (Melko-nian et al. 1991). Images of this type have longbeen viewed as support for cisternal progres-sion/maturation (Becker et al. 1995), and theevidence remains persuasive.

At the same time, a basic cisternal progres-sion/maturation model is unable to explain allof the data. There is growing evidence that het-erotypic tubular connections are important forGolgi traffic in mammalian cells. Such connec-tions may play equally important roles in othercell types, and in microsporidia, they may haveevolved as the dominant mode of Golgi traffic.We therefore propose Model 3 (Cisternal Pro-gression/Maturation with Heterotypic Tubular

Figure 6. Two views of Golgi stacks in the alga Scherf-felia dubia. (A) Thin-section electron micrograph ofthe apical region of a S. dubia cell. The two Golgistacks (G) are separated by the nucleus (n). Smallarrowheads indicate the transitional ER, which isthe site of ER exit. Electron-dense scales can be seenin Golgi cisternae but not in peri-Golgi vesicles. Scalebar, 1.0 mm. (Panel A adapted from Perasso et al.[2000] and reprinted with permission from Springer#2000.) (B) An electron tomographic slice of a sin-gle S. dubia Golgi stack next to a transitional ER site(tER). Superimposed on this slice is a 3D model ofthe Golgi-associated vesicles, which were interpretedas falling into five classes: two morphologically dis-tinct classes of COPI vesicles (purple and green),COPII vesicles (gold), secretory vesicles (blue), andclathrin-coated vesicles (pink). Scale bar, 100 nm.(Panel B reproduced, with permission, from Staehe-lin and Kang [2008].)





Transport) as a working hypothesis to guidefuture experimentation. Among the centralissues to be explored are the contents and direc-tionality of COPI vesicles (Rabouille and Klum-perman 2005; Rothman 2010), the possibleexistence of a long-lived TGN or post-TGNcompartment (Glick and Nakano 2009), andthe role of Rab GTPases in Golgi dynamics(Pfeffer 2010).

ACKNOWLEDGMENTS

B.S.G. acknowledges support from NIH grantGM-61156. A.L. would like to thank Telethon,AIRC (Associazione Italiana per la Ricerca sulCancro), the MIUR (Ministero dell’ Universita’e della Ricerca), the EU (FP7), and the Fonda-zione per la Ricerca sulla Fibrosi Cistica forfinancial support.

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Models for Golgi Traffic: A Critical Assessment

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