PMID:19270693

Citation	Zhong, Y, Wang, QJ, Li, X, Yan, Y, Backer, JM, Chait, BT, Heintz, N and Yue, Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat. Cell Biol. 11:468-76
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.
Links	PubMed PMC2664389 Online version:10.1038/ncb1854
Keywords	Adaptor Proteins, Signal Transducing/chemistry; Adaptor Proteins, Signal Transducing/metabolism; Amino Acid Sequence; Animals; Apoptosis Regulatory Proteins; Autophagy; Cell Membrane/metabolism; Cell Membrane/ultrastructure; Endosomes/metabolism; Endosomes/ultrastructure; Green Fluorescent Proteins/metabolism; HeLa Cells; Humans; Lysosomes/metabolism; Lysosomes/ultrastructure; Mice; Molecular Sequence Data; NIH 3T3 Cells; Phosphatidylinositol 3-Kinases/metabolism; Phosphatidylinositol Phosphates/metabolism; Protein Binding; Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:BAKOR		GO:0006914: autophagy	ECO:0000315:		P		As shown in Figure 2a, knockdown of Atg14L leads to a buildup of autophagy substrates that accumulate only in the event of autophagy impairment, as opposed to the wild type where the substrate levels are negligible.	complete CACAO 9054
MOUSE:BAKOR	involved_in	GO:0006914: autophagy	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

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