Enhanced SnapShot: Endosome-to-Golgi Retrieval

See online version for legend and references. The endosome-to-Golgi retrieval pathway regulates the localization of many important membrane proteins, is highly conserved in eukaryotes, and represents a key point of intersection of the secretory and endocytic pathways. Endosome-to-Golgi transport plays a role in diverse processes such as lysosome biogenesis, transcytosis, Wnt signaling, and amyloid precursor protein localization and processing. The best characterized " cargo " in the endosome-to-Golgi pathway in mammals is the cation-independent mannose 6-phosphate receptor (CIMPR) that mediates sorting of lysosomal hydrolases into clathrin-coated vesicles at the Golgi/trans-Golgi network (TGN). Endosome-to-Golgi retrieval essentially comprises three discrete steps involving (1) cargo selection, (2) tubule formation and transport, and (3) tethering/docking at the Golgi/TGN; the picture is complicated, however, by evidence of at least two endosome-to-Golgi retrieval pathways that may function in series or in parallel. The three steps are shown in the figure along with some of the key machinery required for each step. Studies in yeast (Saccharomyces cerevisiae) and mammalian cells have identified much of the core machinery that mediates endosome-to-Golgi retrieval and have revealed mechanistic similarities with other membrane trafficking pathways. In yeast, five proteins, Vps5p, Vps17p, Vps26p, Vps29p, and Vps35p, assemble into the retromer complex and localize to endosomal membranes to mediate endosome-to-Golgi retrieval of the vacuolar hydrolase receptor, Vps10p. Retromer can be biochemically dissected into two subcomplexes: the cargo-selective Vps35p/Vps29p/Vps26p subcomplex and the sorting nexin (Snx) subcomplex comprising Vps5p/Vps17p in yeast. In mammals, the Vps35, Vps29, and Vps26 proteins form a stable trimer that binds cargo and dynamically associates with sorting nexins, Snx1 and Snx2 (along with Snx5 and Snx6). The Snx proteins contain phosphotidylinositol 3-phosphate (PtdIns 3P)-binding PX domains that are necessary for membrane recruitment, demonstrating a key role for PtdIns 3-kinase activity in regulating retromer activity. Recruitment of the cargo-selective retromer subcomplex (Vps35/29/26) is catalyzed by the small GTPase Rab7. The retromer-interacting protein, TBC1D5, can displace the Vps35/29/26 complex from the membrane and may function as a GTPase-stimulating protein (GAP) for Rab7. The recognition of cargo proteins by retromer involves hydrophobic motifs such as the Trp-Leu-Met (WLM) motif that is conserved in the cytoplasmic tail of CIMPR proteins and that has been shown to be required for endosome-to-Golgi retrieval of a reporter protein carrying the CIMPR tail. Sorting of cargo into endosome tubules occurs through the concerted action of the Vps35/29/26 complex with the Snx proteins. The Snx proteins drive tubule formation via …