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Bro1 Stimulates Vps4 Activity To Promote Intralumenal Vesicle Formation During Multivesicular Body Biogenesis

Chun-Che Tseng, Shirley Dean, Brian A. Davies, Ishara F. Azmi, Natalya Pashkova, Johanna A. Payne, Jennifer Staffenhagen, Matt West, Robert C. Piper, Greg Odorizzi, David J. Katzmann

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AbstractEndosomal sorting complexes required for transport (ESCRT-0, -I, -II, -III) execute cargo sorting and intralumenal vesicle (ILV) formation during conversion of endosomes to multivesicular bodies (MVBs). The AAA-ATPase Vps4 regulates the ESCRT-III polymer to facilitate membrane remodeling and ILV scission during MVB biogenesis. Here we show that the conserved V domain of ESCRT-associated protein Bro1 (the yeast homolog of mammalian proteins ALIX and HD-PTP) directly stimulates Vps4. This activity is required for MVB cargo sorting. Furthermore, the Bro1 V domain alone supports Vps4/ESCRT-driven ILV formation in vivo without efficient MVB cargo sorting. These results reveal a novel activity of the V domains of Bro1 homologs in licensing ESCRT-III-dependent ILV formation and suggest a role in coordinating cargo sorting with membrane remodeling during MVB sorting. Moreover, ubiquitin binding enhances V domain stimulation of Vps4 to promote ILV formation via the Bro1/Vps4/ESCRT-III axis, uncovering a novel role for ubiquitin during MVB biogenesis in addition to facilitating cargo recognition.SummaryCargo sorting is coordinated with intralumenal vesicle budding during ESCRT-mediated multivesicular body biogenesis. Bro1 V domain stimulates Vps4 to promote ESCRT-III-driven intralumenal vesicle formation in a manner required for this coordinated process.