Autophagy is a highly complicated process with participation of large numbers of autophagy-related proteins. Under nutrient starvation, autophagy promotes cell survival by breaking down nonessential cellular components for recycling use. However, due to its high complexity, molecular mechanism of autophagy is still not fully understood. In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. TM9SF4

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... eins were abundantly expressed in the kidney, especially in renal proximal tubular epithelial cells. At subcellular cells, TM9SF4 proteins were mostly localized in lysosome, Golgi, late endosome and autophagosome. Knockdown of TM9SF4 with TM9SF4-shRNAs markedly reduced the starvation-induced autophagy in HEK293 cells, the effect of which persisted in the presence of bafilomycin A1. TM9SF4-shRNAs also substantially attenuated the starvation-induced mTOR inactivation. In animal model, starvation was able to induce LC3-II accumulation and cause mTOR inactivation in renal cortical tissue in wild-type mice, the effect of which was minimal/absent in TM9SF4 knockout (TM9SF4 −/− ) mice. Co-immunoprecipitation and proximity ligation assay demonstrated physical interaction of TM9SF4 proteins with mTOR. In addition, knockdown or knockout of TM9SF4 reduced the starvationinduced cell death in HEK293 cells and animal model. Taken together, the present study identifies TM9SF4 as a novel autophagyrelated protein. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death.