SESN2 (sestrin 2) functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway, a master controller of cellular growth and metabolism. In the absence of leucine, SESN2 binds to the GATOR2 complex and inhibits mTORC1 signaling 1. When leucine is present, it binds directly to SESN2 with a dissociation constant of 20 micromolar, causing a conformational change that disrupts the SESN2-GATOR2 interaction and allows mTORC1 activation 1. The GATOR2 complex adopts a large, cage-like architecture that mediates interactions with SESN2 and other nutrient sensors 2. Beyond nutrient sensing, SESN2 serves as a stress-inducible metabolic regulator with cytoprotective functions. It can facilitate NFE2L2-mediated oxidative stress responses by promoting autophagic degradation of KEAP1 through SQSTM1 3. SESN2 is also involved in organelle-specific autophagy processes that are important for maintaining cellular homeostasis and may have therapeutic relevance in inflammatory diseases 4. The protein's leucine-binding capacity is essential for leucine-mediated mTORC1 activation in cells, positioning SESN2 as a critical node in amino acid sensing and cellular stress responses 1.