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Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG

Nature Cell Biology volume 8, pages 688–698 (2006)Cite this article

Abstract

Autophagy, the degradation of cytoplasmic components, is an evolutionarily conserved homeostatic process involved in environmental adaptation, lifespan determination and tumour development. The tumor suppressor Beclin1 is part of the PI(3) kinase class III (PI(3)KC3) lipid-kinase complex that induces autophagy. The autophagic activity of the Beclin1–PI(3)KC3 complex, however, is suppressed by Bcl-2. Here, we report the identification of a novel coiled–coil UV irradiation resistance-associated gene (UVRAG) as a positive regulator of the Beclin1–PI(3)KC3 complex. UVRAG, a tumour suppressor candidate that is monoallelically mutated at high frequency in human colon cancers, associates with the Beclin1–Bcl-2–PI(3)KC3 multiprotein complex, where UVRAG and Beclin1 interdependently induce autophagy. UVRAG-mediated activation of the Beclin1–PI(3)KC3 complex promotes autophagy and also suppresses the proliferation and tumorigenicity of human colon cancer cells. These results identify UVRAG as an essential component of the Beclin1–PI(3)KC3 lipid kinase complex that is an important signalling checkpoint for autophagy and tumour-cell growth.

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Figure 1: Identification of Beclin1, PI(3)KC3 and UVRAG as vBcl-2 binding proteins.
Figure 2: UVRAG Interacts with Beclin1, PI(3)KC3 and vBcl-2.
Figure 3: Autophagosome formation induced by UVRAG expression.
Figure 4: UVRAG expression increases the volume and relative enzymatic activity of lysosomal compartments.
Figure 5: Beclin1 and UVRAG interdependently induce autophagosome formation.
Figure 6: Increase of the Beclin1–PI(3)KC3 interaction and PI(3)KC3 activity by UVRAG.
Figure 7: Effect of UVRAG ectopic expression on growth groperties.
Figure 8: Schematic representation of a model for a cross-regulatory mechanism of Beclin1-mediated modulation of autophagy.

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Acknowledgements

This work was partly supported by U.S. Public Health Service grants CA82057, CA91819, CA31363, CA106156, and RR00168 (JUJ), the Creative Research Initiative of Korea Ministry of Science and Technology (B.-H.O and B.-S.K.). P.F. is a Leukemia & Lymphoma Society Fellow. We thank B. Levine, M.J. Hardwick, S. Virgin, S. Field, N. Mizushima, T. Yoshimori, J. Backer and Y. Ohsumi for providing reagents, T. Seo and S. Dann for helping with the PI3KC3 assay, S. Gygi for mass spectrometry, J. Mackey for performing electron microscopy, and T.C. Taylor and K.G. Toney for helping with manuscript preparation. Finally, we thank all members of Tumor Virology Division for discussions.

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Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, 01772, MA, USA

    Chengyu Liang, Pinghui Feng & Jae U. Jung

  2. Department of Life Sciences, Center for Biomolecular Recognition, Pohang University of Science and Technology, Pohang, 790-784, Kyungbuk, Korea

    Bonsu Ku & Byung-Ha Oh

  3. Department of Biochemistry, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Iris Dotan & Dan Canaani

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Liang, C., Feng, P., Ku, B. et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 8, 688–698 (2006). https://doi.org/10.1038/ncb1426

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