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

Nature Cell Biology volume 9, pages 1142–1151 (2007)Cite this article

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.

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Figure 1: Loss of Bif-1 suppresses caspase-independent cell death induced by nutrition deprivation.
Figure 2: Inhibition of autophagy enhances caspase-3 activation, but suppresses caspase-independent cell death.
Figure 3: Loss of Bif-1 inhibits autophagy.
Figure 4: Bif-1 localizes to autophagosomes.
Figure 5: Bif-1 interacts with Beclin 1 through UVRAG.
Figure 6: Overexpression of the SH3 domain of Bif-1 but not of Endophilin A1 suppresses autophagosome formation.
Figure 7: Loss of Bif-1 suppresses PI(3)KC3 activation during nutrient starvation.
Figure 8: Knockout of Bif-1 enhances spontaneous tumorigenesis in mice.

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Acknowledgements

We thank: E. Haller for assistance with electron microscopic analyses; G. Gao for statistical help; C. Meyerkord and R. Youle for critical reading of the manuscript; and D. C. S. Huang, B. Levine, N. Mizushima, G. Nolan, G. Reuther and T. Yoshimori for reagents. This work was supported by grants from the National Institutes of Health (NIH) and American Cancer Society (ACS) to H.-G.W. and fellowships from the Uehara Memorial Foundation and Japan Society for the Promotion of Science (JSPS) to Y.T.

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Authors and Affiliations

  1. H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, 33612, FL, USA

    Yoshinori Takahashi, Domenico Coppola, Norimasa Matsushita, Hernani D. Cualing, Mei Sun, Yuya Sato, Jin Q. Cheng, James J. Mul, W. Jack Pledger & Hong-Gang Wang

  2. Harvard Medical School, 1 Pine Hill Drive, Southborough, 01772, MA, USA

    Chengyu Liang & Jae U. Jung

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Correspondence to Hong-Gang Wang.

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Takahashi, Y., Coppola, D., Matsushita, N. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 9, 1142–1151 (2007). https://doi.org/10.1038/ncb1634

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