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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    • "Indeed, a growing list of membrane trafficking regulators impinges on autophagosome formation and maturation. These have been reviewed in detail recently (Lamb et al, 2013a,b) and include small GTPases (Itoh et al, 2008; Zoppino et al, 2010; Moreau et al, 2012), RabGAPs (GTPase activating proteins) (Itoh et al, 2011; Longatti et al, 2012; Popovic et al, 2012), SNARE proteins (Itakura et al, 2012; Hamasaki et al, 2013; Puri et al, 2013; Moreau et al, 2014), sorting nexins (Knaevelsrud et al, 2013) and vesicle tethering complexes (Liang et al, 2008). Unpicking the functions of these components will permit a better understanding of the mechanisms of autophagosome formation. "
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    ABSTRACT: Macroautophagy requires membrane trafficking and remodelling to form the autophagosome and deliver its contents to lysosomes for degradation. We have previously identified the TBC domain-containing protein, TBC1D14, as a negative regulator of autophagy that controls delivery of membranes from RAB11-positive recycling endosomes to forming autophagosomes. In this study, we identify the TRAPP complex, a multi-subunit tethering complex and GEF for RAB1, as an interactor of TBC1D14. TBC1D14 binds to the TRAPP complex via an N-terminal 103 amino acid region, and overexpression of this region inhibits both autophagy and secretory traffic. TRAPPC8, the mammalian orthologue of a yeast autophagy-specific TRAPP subunit, forms part of a mammalian TRAPPIII-like complex and both this complex and TBC1D14 are needed for RAB1 activation. TRAPPC8 modulates autophagy and secretory trafficking and is required for TBC1D14 to bind TRAPPIII. Importantly, TBC1D14 and TRAPPIII regulate ATG9 trafficking independently of ULK1. We propose a model whereby TBC1D14 and TRAPPIII regulate a constitutive trafficking step from peripheral recycling endosomes to the early Golgi, maintaining the cycling pool of ATG9 required for initiation of autophagy.
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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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    • "An autophagosome matures into an autolysosome by sequential fusion with endosomes and with lysosomes, the contents of which are degraded by hydrolases therein. It is reported that autolysosome formation is related to UVRAG and expression of lysosomal-associated membrane protein 2 (Lamp-2) (Liang et al., 2008; Fortunato et al., 2009). "
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