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

Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Nature Cell Biology (Impact Factor: 19.68). 08/2008; 10(7):776-87. DOI: 10.1038/ncb1740
Source: PubMed


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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    • "Evidence supporting this notion came from the experiments showing that degradation of the autophagic substrate p62/SQSTM1 was retarded and that the autolysosome-liable GFP fluorescence of the mRFP-GFP-LC3 reporter protein was not lost in spite of enhanced LC3 lipidation . Beclin1, again, is likely the target responsible for the deficient autophagosome maturation in PLP2-TM expressing cells, given its involvement in the UVRAG-containing PI3K complex that controls fusion between autophagosmes and lysosomes (Kang et al., 2011; Liang et al., 2008). Of note, accumulating evidence suggests that Beclin1 is a prime target for viruses that manipulate the autophagy pathway (Munz, 2011). "
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