The curious status of the Golgi apparatus.

The available evidence suggests the following working hypotheses. (1) COPII vesicles fuse to form ERGIC clusters, which fuse in turn to form a new Golgi cisterna. (2) Each cisterna progresses through the stack and ultimately fragments into transport vesicles. (3) All resident Golgi proteins are continually recycled via retrograde vesicles. This vesicular transport drives the maturation of Golgi cisternae.Each of these hypotheses raises a new set of questions. First, what nucleates the formation of an ERGIC cluster? Is a cytosolic scaffold involved? How does the cell decide when a given ERGIC cluster has been completed, so that subsequent COPII vesicles will contribute to forming a new cluster? What determines the number of ERGIC clusters that fuse to generate a cisterna? Second, is cisternal progression an active process, or do the cisternae simply diffuse? What signal induces a cisterna to undergo terminal maturation at the TGN? Third, how do COPI vesicles incorporate all of the diverse proteins that reside in the Golgi? Are there multiple classes of COPI vesicles (Orci et al. 1997xBidirectional transport by distinct populations of COPI-coated vesicles. Orci, L, Stamnes, M, Ravazzola, M, Amherdt, M, Perrelet, A, Sollner, T.H, and Rothman, J.E. Cell. 1997; 90: 335–349Abstract | Full Text | Full Text PDF | PubMed | Scopus (296)See all ReferencesOrci et al. 1997)? In addition to COPI vesicles, other vesicles apparently retrieve proteins that cycle between the TGN and later compartments of the endomembrane system (Munro 1998xLocalization of proteins to the Golgi apparatus. Munro, S. Trends Cell Biol. 1998; 8: 11–15Abstract | Full Text PDF | PubMed | Scopus (194)See all ReferencesMunro 1998). How is this TGN recycling pathway integrated with intra-Golgi recycling?These questions, which concern the mechanics of Golgi operation, tend to mask the embarrassing fact that we still do not understand how the structure of the Golgi relates to its function. For example, why are Golgi cisternae organized into stacks in most cell types, but dispersed throughout the cytoplasm in S. cerevisiae? One can only speculate that the sites of cisternal assembly are arranged differently in S. cerevisiae than in other eukaryotes. And why do Golgi cisternae have similar diameters in all cells (Farquhar and Palade 1981xThe Golgi apparatus (complex) - (1954–1981) - from artifact to center stage. Farquhar, M.G and Palade, G.E. J. Cell Biol. 1981; 91: 77s–103sCrossref | PubMedSee all ReferencesFarquhar and Palade 1981)? A possible explanation is that if cisternae were larger, vesicular transport would be too slow to effect maturation. Vesicles bud from the cisternal rims, so the maximal rate of vesicular transport will be proportional to a cisterna's diameter, whereas the surface area and volume of a cisterna are roughly proportional to the square of its diameter. Thus, the larger the cisterna, the more slowly its contents will turn over by vesicle-driven maturation.Perhaps the most fundamental mystery concerns the basic organization of the Golgi. Why is this organelle subdivided into cisternae in the first place, and why does the number of cisternae per stack range from about 3 to 30 in various cell types (Mollenhauer and Morre 1991xPerspectives on Golgi apparatus form and function. Mollenhauer, H.H and Morre, D.J. J. Electron Microsc. Tech. 1991; 17: 2–14Crossref | PubMed | Scopus (42)See all ReferencesMollenhauer and Morre 1991)? An interesting theory is that the Golgi stack serves as an iterative recycling device for bringing resident ER proteins back to the ER (Rothman and Wieland 1996xProtein sorting by transport vesicles. Rothman, J.E and Wieland, F.T. Science. 1996; 272: 227–234Crossref | PubMedSee all ReferencesRothman and Wieland 1996). However, resident ER proteins rarely travel beyond the first cisterna or two (Pelham 1995xSorting and retrieval between the endoplasmic reticulum and Golgi apparatus. Pelham, H. Curr. Opin. Cell Biol. 1995; 7: 530–535Crossref | PubMed | Scopus (130)See all ReferencesPelham 1995), so it seems unlikely that cells would need extended Golgi stacks solely to recycle ER proteins. An alternative idea comes from recognizing that the Golgi is a carbohydrate factory, with the cisternal stack being analogous to an assembly line (39xThe Golgi complex (in vitro veritas?) . Mellman, I and Simons, K. Cell. 1992; 68: 829–840Abstract | Full Text PDF | PubMed | Scopus (306)See all References, 28xThe molecular and cell biology of glycosyltransferases. Kleene, R and Berger, E.G. Biochim. Biophys. Acta. 1993; 1154: 283–325Crossref | PubMed | Scopus (173)See all References). Secretory products need to spend enough time on the assembly line for all of the carbohydrate processing steps to be completed. By forcing a cisterna to progress through the entire stack, a cell ensures that the secretory cargo remains in the Golgi long enough to be fully processed (i.e, the stack serves as a “delay timer”). In support of this notion, the number of cisternae in a stack seems to correlate with the complexity of the secretory products being produced by the cell (Becker and Melkonian 1996xThe secretory pathway of protists (spatial and functional organization and evolution) . Becker, B and Melkonian, M. Microbiol. Rev. 1996; 60: 697–721PubMedSee all ReferencesBecker and Melkonian 1996).The new dynamic view of the Golgi may also be applicable to endosomes. Indeed, maturation models have been discussed extensively in the endosome field (24xEndosomes. Helenius, A, Mellman, I, Wall, D, and Hubbard, A. Trends Biochem. Sci. 1983; 8: 245–250Abstract | Full Text PDF | Scopus (248)See all References, 20xMembrane transport in the endocytic pathway. Gruenberg, J and Maxfield, F.R. Curr. Opin. Cell Biol. 1995; 7: 552–563Crossref | PubMed | Scopus (508)See all References). One interpretation of the existing data is that endocytic vesicles fuse homotypically to form early endosomes, which mature into late endosomes and eventually fuse with lysosomes. Hence, many compartments of the endomembrane system seem to be transitory structures that can only be understood in the context of other interacting compartments. So how then do we define the Golgi? Where does it begin and end? Seen in this light, the Golgi acquires a curious status: it is more than just an outgrowth of the ER, yet it is not truly an independent organelle.Is the cisternal maturation model the last word on Golgi organization? Almost certainly not. There is still no consensus about any feature of this model. For example, some investigators propose that COPI vesicles mediate anterograde as well as retrograde transport (Orci et al. 1997xBidirectional transport by distinct populations of COPI-coated vesicles. Orci, L, Stamnes, M, Ravazzola, M, Amherdt, M, Perrelet, A, Sollner, T.H, and Rothman, J.E. Cell. 1997; 90: 335–349Abstract | Full Text | Full Text PDF | PubMed | Scopus (296)See all ReferencesOrci et al. 1997). Even more complicated models emerge from the debate about whether tubular connections between cisternae play a role in transport through the stack (39xThe Golgi complex (in vitro veritas?) . Mellman, I and Simons, K. Cell. 1992; 68: 829–840Abstract | Full Text PDF | PubMed | Scopus (306)See all References, 40xVariations on the intracellular transport theme (maturing cisternae and trafficking tubules) . Mironov, A.A, Weidman, P, and Luini, A. J. Cell Biol. 1997; 138: 481–484Crossref | PubMed | Scopus (117)See all References). In his 1975 monograph, Whaley wrote, “No cellular organelle has been the subject of as many, as long-lasting, or as diverse polemics as the Golgi apparatus.” We are happy to report that this statement is just as true in 1998.‡To whom correspondence should be addressed (e-mail: malhotra@biomail.ucsd.edu).