Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis

Takahashi, Y. et al. Nature Cell Biol. 9, 1142-1151 (2007)

Speaker: 盧怡恬                                                 Time: 13:10~14:00, Nov. 21, 2007

Commentator: 張志鵬 學長                                        Place: Room 601

Abstract:

        Autophagy is a degradation process of cytoplasmic cellular constituents, and it is characterized by sequestration of bulk cytoplasmic proteins and organelles in double-membrane vesicles called autophagosomes⁽¹⁾. Beclin 1, a key component of the class III PI3K complex, is essential forautophagosome formation. Previous studies reported that ultraviolet irradiation resistance-associated gene (UVRAG) directly interacts with the Beclin 1-class III PI3K complex to activate autophagy⁽²⁾, but the molecular mechanism is unclear. Bif-1, also known as Endophilin B1, was found as aBax-binding protein involved in apoptosis, but the role of Bif-1 in autophagy remains unknown. Bif-1 contains a BAR domain which has been shown to control membrane curvature⁽³⁾. In this study, the authors observed a decrease of starvation-induced cell death in Bif-1^-/- mouse embryonic fibroblasts (MEF). During nutrient starvation, inhibition of autophagy enhanced caspase-3 activation, but suppressed caspase-independent cell death in wild-type but not in Bif-1^-/- MEFs. The number of autophagosomes and the processing of LC3-I to LC3-II were decreased when lacking of Bif-1. These effects were overcome by restoration of Bif-1 expression. Bif-1 colocalized with Atg5 and LC3 under nutrition-starvation condition, indicating that Bif-1 is involved in the early stage of autophagosome formation. Furthermore, Bif-1 interacts with Beclin 1 through UVRAG to stimulate the activation of class III PI3K and autophagosome formation. In addition, knockout of Bif-1 enhanced the development of spontaneous tumors in mice. These results suggest that interation between Bif-1 and UVRAG-Beclin 1 complex causes induction of autophagy and suppression of tumorigenesis.

References:

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2.    Liang, C. et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nature Cell Biol. 8, 688–699 (2006).

3.    Mari, M. and Reggiori, F. Shaping membrane into autophagosomes. Nature Cell Biol. 9, 1125–1127 (2007).