Bulk Flow Redux?

et al., 1984). How are they selectively extracted from this dilute solution and shipped to the Golgi apparatus? Before considering current models, the pathway to Graham Warren and Ira Mellman Department of Cell Biology Yale University School of Medicine New Haven, Connecticut 06520-8002 the Golgi needs to be described (Figure 1) (Kaiser and Ferro-Novick, 1998). Cargo proteins exit in COPII-coated vesicles that bud from specialized exit sites known as transitional elements of the ER. As these vesicles unIntroduction The transport and sorting of proteins newly made in the coat, they fuse to form vesiculo-tubular clusters (VTCs, also known as the salvage compartment, the intermediendoplasmic reticulum (ER) has long been a fascinating and contentious issue to those interested in membrane ate compartment, and the ERGIC), which then become coated with COPI coats. COPI-coated vesicles mediate traffic processes. Secretory and membrane proteins, collectively termed “cargo proteins,” exit the ER in vesithe recycling of components back to the ER. These include the membrane components of the vesicle macles targeted to the Golgi apparatus. Transport through the Golgi is often accompanied by extensive posttranschinery itself (such as the p24 family of coat-binding proteins), targeting components (such as the SNAREs), lational modification until the trans-Golgi network (TGN) is reached. Here, cargo is sorted into vesicles bound and any escaped ER proteins appropriately tagged so as to bind directly to the COPI coat itself or indirectly for different destinations including secretory granules, the plasma membrane, and the endosome/lysosome to receptors such as the KDEL receptor. Sorting Models system. Sorting not only involves the separation of cargo proSo how does this step of the pathway separate cargo from resident ER proteins? Two opposing models have teins from those intended for other destinations. It also involves their separation from components of the comdominated the field and can be summarized as follows. First, the bulk flow model (Wieland et al., 1987) puts partments through which they move. The first such separation occurs during transport from the ER to the Golgi the onus for sorting on the ER proteins themselves. Retention signals keep the ER proteins in the ER and apparatus. Cargo proteins typically constitute only a few percent of the many ER proteins that are responsible retrieval signals salvage those few that inadvertently escape. Cargo moves by default and requires no export for their synthesis, translocation, and assembly (Quinn