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Autophagic and endocytic pathways are tightly regulated membrane rearrangement processes that are crucial for homeostasis, development and disease. Autophagic cargo is delivered from autophagosomes to lysosomes for degradation through a complex process that topologically resembles endosomal maturation. Here, we report that a Beclin1-binding autophagic tumour suppressor, UVRAG, interacts with the class C Vps complex, a key component of the endosomal fusion machinery. This interaction stimulates Rab7 GTPase activity and autophagosome fusion with late endosomes/lysosomes, thereby enhancing delivery and degradation of autophagic cargo. Furthermore, the UVRAG-class-C-Vps complex accelerates endosome-endosome fusion, resulting in rapid degradation of endocytic cargo. Remarkably, autophagosome/endosome maturation mediated by the UVRAG-class-C-Vps complex is genetically separable from UVRAG-Beclin1-mediated autophagosome formation. This result indicates that UVRAG functions as a multivalent trafficking effector that regulates not only two important steps of autophagy -autophagosome formation and maturation -but also endosomal fusion, which concomitantly promotes transport of autophagic and endocytic cargo to the degradative compartments.© 2008 Macmillan Publishers Limited. All rights reserved. 6 Correspondence should be addressed to J.U.J. (jaeujung@usc.edu). AUTHOR CONTRIBUTIONS C.L. performed all aspects of this study; L.S., K.I., M.G., Q.L. and P.F. assisted with the experimental design and in collecting the data; E.R., I.V. and V.D. assisted with the autophagic protein degradation and in vitro endosome fusion assay; C.A. provided Vps constructs and their antibodies; C.L. and J.J. organized this study and wrote the paper. All authors discussed the results and commented on the manuscript.Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2010 May 31. Published in final edited form as:Nat Cell Biol. 2008 July ; 10(7): 776-787. doi:10.1038/ncb1740. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAutophagy is a tightly regulated membrane rearrangement process that ensures lysosomedependent bulk degradation of cytosolic proteins or organelles, and is highly conserved in eukaryotic cells, as seen with the endocytic pathway 1 . In response to environmental stresses, portions of cytoplasmic constituents are engulfed by a unique membrane structure, the phagophore, as it elongates to form a double-or multiple-membrane-bound compartment called the autophagosome. Newly synthesized autophagosomes then undergo extensive remodelling to acquire degradative capabilities. The remodelling process, also known as autophagosomal maturation, involves sequential fusion of autophagosomes with endocytic vesicles...