The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease

Abstract

The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient–mTORC1 signalling in multiple diseases. Mechanistic target of rapamycin mTOR complex 1 (mTORC1) is a central regulator of cellular metabolism. Recent studies of the molecular architecture of mTORC1 shed new light on its physiological functions and on the consequences of their dysregulation in cancer, type 2 diabetes and neurodegeneration.