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

Nature cell biology | Jul 1, 2008

http://www.ncbi.nlm.nih.gov/pubmed/18552835

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.

Pubmed ID: 18552835 RIS Download

Mesh terms: Animals | Apoptosis Regulatory Proteins | Autophagy | Cell Line | Endocytosis | Endosomes | Humans | Lysosomes | Membrane Fusion | Membrane Proteins | Mice | Multiprotein Complexes | Phagosomes | Protein Transport | Recombinant Fusion Proteins | Tumor Suppressor Proteins | Vesicular Transport Proteins | rab GTP-Binding Proteins

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI 42999
  • Agency: NIAID NIH HHS, Id: AI069345
  • Agency: NCI NIH HHS, Id: CA106156
  • Agency: NCI NIH HHS, Id: CA31363
  • Agency: NCI NIH HHS, Id: CA82057
  • Agency: NCI NIH HHS, Id: CA91819
  • Agency: NIAID NIH HHS, Id: R01 AI042999
  • Agency: NIAID NIH HHS, Id: R01 AI073099
  • Agency: NIAID NIH HHS, Id: R01 AI073099-02
  • Agency: NCI NIH HHS, Id: R01 CA031363
  • Agency: NHLBI NIH HHS, Id: R01 HL110609
  • Agency: NCRR NIH HHS, Id: RR00168

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