Bro1 stimulates Vps4 to promote intralumenal vesicle formation during multivesicular body biogenesis |
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| Authors: | 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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| Institution: | 1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN ; 2. Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN ; 3. Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA ; 4. Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO |
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| Abstract: | Endosomal 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 homologue 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 homologues 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. |
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