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Recruitment of VPS33A to HOPS by VPS16 Is Required for Lysosome Fusion with Endosomes and Autophagosomes

DOI: 10.1111/tra.12283 DOI Help
PMID: 25783203 PMID Help

Authors: Lena Wartosch (University of Cambridge) , Ufuk G├╝nesdogan (University of Cambridge) , Stephen C. Graham (University of Cambridge) , J. Paul Luzio (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Traffic , VOL 16 (7) , PAGES 727 - 742

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 8547

Open Access Open Access

Abstract: The mammalian homotypic fusion and vacuole protein sorting (HOPS) complex is comprised of six subunits: VPS11, VPS16, VPS18, VPS39, VPS41 and the Sec1/Munc18 (SM) family member VPS33A. Human HOPS has been predicted to be a tethering complex required for fusion of intracellular compartments with lysosomes, but it remains unclear whether all HOPS subunits are required. We showed that the whole HOPS complex is required for fusion of endosomes with lysosomes by monitoring the delivery of endocytosed fluorescent dextran to lysosomes in cells depleted of individual HOPS proteins. We used the crystal structure of the VPS16/VPS33A complex to design VPS16 and VPS33A mutants that no longer bind each other and showed that, unlike the wild-type proteins, these mutants no longer rescue lysosome fusion with endosomes or autophagosomes in cells depleted of the endogenous proteins. There was no effect of depleting either VIPAR or VPS33B, paralogs of VPS16 and VPS33A, on fusion of lysosomes with either endosomes or autophagosomes and immunoprecipitation showed that they form a complex distinct from HOPS. Our data demonstrate the necessity of recruiting the SM protein VPS33A to HOPS via its interaction with VPS16 and that HOPS proteins, but not VIPAR or VPS33B, are essential for fusion of endosomes or autophagosomes with lysosomes.

Journal Keywords: Autophagy; Corvet; Endocytosis; Hops; Lysosomes; Sm Protein; Tethering Factor; Vps16; Vps33A

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/09/2015 13:00

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