The emerging shape of the ESCRT machinery

Central to the function of the MVB pathway for trafficking to lysosomes are the endosomal sorting complex required for transport-0 (ESCRT-0), -I, -II and –III complexes, which are represented in all eukaryotic taxa. Ubiquitylation is the best characterised signal for entry into this pathway, and all of the ESCRTs, except for ESCRT-III, recognize ubiquitin.The ESCRT-0 complex recruits ubiquitylated cargo to flat clathrin-coated dynamic microdomains on endosomes and is essential to recruiting ESCRT-I. The endosomal recruitment of ESCRT-0 is mediated by binding to 3-phosphoinosides, which are enriched in early endosome membranes.ESCRT-I is built around a heterotrimeric core to which flexibly connected modules that recognize ubiquitylated cargo and the downstream ESCRT-II complex are connected. This complex is essential for intralumenal vesicle formation and vacuolar stability.The four-subunit ESCRT-II core complex is built from winged-helix domains. The subunits link directly to the downstream VPS20 subunit of ESCRT-III, whereas the N-terminal GLUE domain of VPS36 recognizes ubiquitin, 3-phosphoinositides and, in yeast, the upstream ESCRT-I.ESCRT-III subunits are represented in all eukaryotic taxa. These subunits heterodimerize via a long N-terminal helical hairpin to form lattices on endosomal membranes that require the AAA+ ATPase VPS4 for subsequent disassembly. The lattice has been proposed to facilitate membrane curvature and the formation of intralumenal vesicles.De-ubiquitinases are recruited by ESCRT-III and can remove ubiquitin from cargo before and after it is committed to entry into intralumenal vesicles.