SESN2
Description
The SESN2 (sestrin 2) is a protein-coding gene located on chromosome 1.
SESN2, also known as Hi95, is a protein that in humans is encoded by the SESN2 gene. This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and survival. This protein may be involved in cellular response to different stress conditions. The Sestrins constitute a family of evolutionarily-conserved stress-inducible proteins that suppress oxidative stress and regulate adenosine monophosphate-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. By virtue of these activities, the Sestrins serve as important regulators of metabolic homeostasis. Accordingly, inactivation of Sestrin genes in invertebrates resulted in diverse metabolic pathologies, including oxidative damage, fat accumulation, mitochondrial dysfunction and muscle degeneration that resemble accelerated tissue aging. The NMDA receptor antagonist ketamine has been found to activate the mammalian target of rapamycin complex 1 (mTORC1) pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects. NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression. The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.
SESN2 functions as an intracellular leucine sensor that negatively regulates the mTORC1 signaling pathway through the GATOR complex. In the absence of leucine, SESN2 binds the GATOR2 subcomplex and prevents mTORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2, thereby activating the TORC1 signaling pathway. SESN2 also plays a role in protection against oxidative and genotoxic stresses. It may negatively regulate protein translation in response to endoplasmic reticulum stress, via mTORC1. It may positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1. SESN2 may also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress. Moreover, SESN2 may prevent the accumulation of reactive oxygen species (ROS) through the alkylhydroperoxide reductase activity born by the N-terminal domain of the protein. SESN2 was originally reported to contribute to oxidative stress resistance by reducing PRDX1. However, this could not be confirmed.
SESN2 is also known as HI95, SES2, SEST2.
