UVRAG TARGETS THE HOPS COMPLEX

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autophagic and endocytic pathways are tightly regulated membrane rearrangement processes that are crucial for cellular homeostasis, development and disease induction. Autophagic cargoes are delivered from autophagosomes to lysosomes for degradation via a complex process that topologically resembles endosomal maturation. Here, we report that a Beclin1-binding autophagic tumour suppressor, UVRAG, interacts with the HOPS tethering complex, a key component of the endosomal fusion machinery. This interaction stimulates Rab7 GTPase activity and autophagosome fusion with late endosomes and lysosomes, thereby enhancing autophagic cargo delivery and degradation. Furthermore, the UVRAG-HOPS complex accelerates intracellular endosome-endosome fusion, resulting in rapid degradation of endocytic cargoes. AIDS related.