Mechanisms of mTORC1 signaling to protein degradation pathways

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The mechanistic target of rapamycin complex 1 (mTORC1) is the nutrient sensing machinery that plays central roles in regulating cell growth and metabolism. Disturbance of mTORC1 functions is associated with human diseases, such as cancer, diabetes, and neurodegeneration, and age-related pathologies. Despite the recent progress in our knowledge on the mTORC1 pathway, how mTORC1 coordinates diverse downstream processes remains poorly understood. Our recent studies revealed that mTORC1 actively engages in regulating protein degradation beyond its role in autophagy. mTORC1 promotes a shift of proteasome population to the immunoproteasome, an inducible type of proteasome, which facilitates removal of a selective group of proteins. We also found that mTORC1 regulates degradation of plasma membrane proteins, such as EGF receptor, via the endocytic pathway. These findings suggest that mTORC1 has a broad range of functions in cellular protein degradation. Better understanding the expanded roles of mTORC1 in protein degradation will have high impact in a wide range of research and will provide novel insight into better therapeutic strategies to treat human diseases associated with mTORC1 dysregulation. The goal of our research program in the next five years is to determine the mechanisms by which mTORC1 regulates protein degradation via three different pathways. First, we will define the mechanisms through which the mTORC1-ULK1 pathway regulates autophagy induction, phagophore nucleation, autophagic membrane fusion with lysosomes, and lysosome reformation. We will extensively investigate the roles of mTORC1- and ULK1-mediated interactions and phosphorylations in regulation of autophagy processes. Using cutting-edge cell imaging techniques and genome-editing tools, we will determine dynamic changes of composition, recruitment, and localization/colocalization of endogenous autophagy proteins during the formation of phagophore and autophagosome. Second, we will define the mechanisms through which mTORC1 regulates the endosome-lysosomal pathway. We will identify key endosomal factors and their interactions and phosphorylations regulated by mTORC1 and determine their roles in endocytic degradation of cell surface proteins. Third, we will elucidate the roles of the immunoproteasome in mediating mTORC1 signaling to regulate cell physiology and metabolism. We will identify proteins that are preferentially digested by the immunoproteasome. We will determine the functional significance of those preferential degradations, aiming to elucidate previously-unknown mechanisms for cellular response to stress and growth signals. Through these directions of research, our research program will advance the fundamental knowledge on mTOR functions in coordinating nutrient, growth and stress status with the membrane-associated protein degradation pathways and the proteasome machinery, and provide novel insight into the pathogenesis of human diseases associated with mTORC1 dysregulation.