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      Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex.

      Nature cell biology

      chemistry, Adaptor Proteins, Signal Transducing, metabolism, Amino Acid Sequence, Animals, Apoptosis Regulatory Proteins, Autophagy, Cell Membrane, ultrastructure, Endosomes, Green Fluorescent Proteins, HeLa Cells, Humans, Lysosomes, Mice, Molecular Sequence Data, NIH 3T3 Cells, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Protein Binding, Proteins

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          Abstract

          Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.

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          Author and article information

          Journal
          19270693
          2664389
          10.1038/ncb1854

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