Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism

Abstract The branched chain amino acids (BCAAs: leucine, isoleucine, valine) are essential amino acids that function as catabolic substrates and signaling molecules via mTORC1. While individual BCAAs have unique roles in organismal and cellular physiology, the mechanisms underlying their individual effects remain poorly understood. We demonstrate that the three BCAAs have distinct roles in T cell biology. We find that isoleucine and valine are necessary and sufficient for quiescence exit and cell division, whereas leucine is dispensable. Mechanistically, these effects are independent of their diverging catabolic fates and instead due to differential sensing of leucine and isoleucine/valine by mTOR and c-Myc. While isoleucine and valine are necessary and sufficient for c-Myc expression, mTORC1 leucine-sensing represses c-Myc and proliferation during BCAA restriction. Together, we find that the discrete sensing of the BCAAs uncouples two major anabolic regulators, mTORC1 and c-Myc, in cell growth. This provides mechanistic insight into the distinct roles of the BCAAs in cell physiology, highlighting divergent BCAA sensing rather than catabolism, and offering a new lens to appreciate their impact on immunity and pathophysiology.