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

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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.