UBAP1 Is a Component of an Endosome-Specific ESCRT-I Complex that Is Essential for MVB Sorting

Endosomal sorting complexes required for transport (ESCRTs) regulate several events involving membrane invagination, including multivesicular body (MVB) biogenesis, viral budding, and cytokinesis [1]. In each case, upstream ESCRTs combine with additional factors, such as Bro1 proteins [2-4], to recruit ESCRT-III and the ATPase VPS4 in order to drive membrane scission [5]. A clue to understanding how such diverse cellular processes might be controlled independently of each other has been the identification of ESCRT isoforms. Mammalian ESCRT-I comprises TSG101, VPS28, VPS37A-D [6-8], and MVB12A/B [9]. These could generate several ESCRT-I complexes, each targeted to a different compartment and able to recruit distinct ESCRT-III proteins. Here we identify a novel ESCRT-I component, ubiquitin-associated protein 1 (UBAP1), which contains a region conserved in MVB12 [10]. UBAP1 binds the endosomal Bro1 protein His domain protein tyrosine phosphatase (HDPTP) [4], but not Alix, a Bro1 protein involved in cytokinesis [11,12]. UBAP1 is required for sorting EGFR to the MVB and for endosomal ubiquitin homeostasis, but not for cytokinesis. UBAP1 is part of a complex that contains a fraction of total cellular TSG101 and that also contains VPS37A but not VPS37C. Hence, the presence of UBAP1, in combination with VPS37A, defines an endosome-specific ESCRT-I complex.