PMID:17891140

Citation	Takahashi, Y, Coppola, D, Matsushita, N, Cualing, HD, Sun, M, Sato, Y, Liang, C, Jung, JU, Cheng, JQ, Mulé, JJ, Pledger, WJ and Wang, HG (2007) Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat. Cell Biol. 9:1142-51
Abstract	Autophagy is an evolutionarily conserved 'self-eating' process. Although the genes essential for autophagy (named Atg) have been identified in yeast, the molecular mechanism of how Atg proteins control autophagosome formation in mammalian cells remains to be elucidated. Here, we demonstrate that Bif-1 (also known as Endophilin B1) interacts with Beclin 1 through ultraviolet irradiation resistance-associated gene (UVRAG) and functions as a positive mediator of the class III PI(3) kinase (PI(3)KC3). In response to nutrient deprivation, Bif-1 localizes to autophagosomes where it colocalizes with Atg5, as well as microtubule-associated protein light chain 3 (LC3). Furthermore, loss of Bif-1 suppresses autophagosome formation. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, both the BAR and SH3 domains are required for Bif-1 to activate PI(3)KC3 and induce autophagosome formation. We also observed that Bif-1 ablation prolongs cell survival under starvation conditions. Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumours in mice. These findings suggest that Bif-1 joins the UVRAG-Beclin 1 complex as a potential activator of autophagy and tumour suppressor.
Links	PubMed PMC2254521 Online version:10.1038/ncb1634
Keywords	Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Apoptosis Regulatory Proteins; Autophagy/genetics; Autophagy/physiology; COS Cells; Caspase 3/metabolism; Cell Line; Cercopithecus aethiops; Green Fluorescent Proteins/genetics; Green Fluorescent Proteins/metabolism; HeLa Cells; Humans; Immunoprecipitation; Mice; Mice, Knockout; Microscopy, Confocal; Microscopy, Fluorescence; Microscopy, Immunoelectron; Neoplasms/genetics; Neoplasms/metabolism; Neoplasms/pathology; Phagosomes/genetics; Phagosomes/metabolism; Phagosomes/ultrastructure; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Proteins/genetics; Proteins/metabolism; RNA Interference; Transfection; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism
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