Function
Sestrin 2 (SESN2) functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In the absence of leucine, SESN2 binds to the GATOR subcomplex GATOR2, preventing TORC1 signaling. The binding of leucine to SESN2 disrupts its interaction with GATOR2, thereby activating the TORC1 signaling pathway. This stress-inducible metabolic regulator also plays a crucial role in protecting cells against oxidative and genotoxic stresses. It may negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1. Additionally, SESN2 may positively regulate transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1. Furthermore, it may mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Notably, SESN2 may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity of its N-terminal domain. While initially reported to contribute to oxidative stress resistance by reducing PRDX1, this finding could not be definitively confirmed.