Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking

C Liang, J Lee, KS Inn, MU Gack, Q Li, EA Roberts… - Nature cell …, 2008 - nature.com
C Liang, J Lee, KS Inn, MU Gack, Q Li, EA Roberts, I Vergne, V Deretic, P Feng, C Akazawa…
Nature cell biology, 2008nature.com
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 …
Abstract
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.
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