Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis.
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.
Takahashi
Yoshinori
Y
H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive. Tampa, FL 33612, USA.
Coppola
Domenico
D
Matsushita
Norimasa
N
Cualing
Hernani D
HD
Sun
Mei
M
Sato
Yuya
Y
Liang
Chengyu
C
Jung
Jae U
JU
Cheng
Jin Q
JQ
Mulé
James J
JJ
Pledger
W Jack
WJ
Wang
Hong-Gang
HG
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D053148:Caspase 3; D049452:Green Fluorescent Proteins; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D025521:Tumor Suppressor Proteins; C115010:Becn1 protein, mouse; C486100:Sh3glb1 protein, mouse; C512859:UVRAG protein, mouse