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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

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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