SESN1
Description
The SESN1 (sestrin 1) is a protein-coding gene located on chromosome 6.
Sestrin 1, also known as p53-regulated protein PA26, is a protein that in humans is encoded by the SESN1 gene. This gene encodes a member of the sestrin family. Sestrins are induced by the p53 tumor suppressor protein and play a role in the cellular response to DNA damage and oxidative stress. The encoded protein mediates p53 inhibition of cell growth by activating AMP-activated protein kinase, which results in the inhibition of the mammalian target of rapamycin protein. The encoded protein also plays a critical role in antioxidant defense by regenerating overoxidized peroxiredoxins, and the expression of this gene is a potential marker for exposure to radiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.
SESN1 acts as an intracellular leucine sensor, negatively controlling the TORC1 signaling pathway via the GATOR complex. In the absence of leucine, SESN1 binds to the GATOR2 subcomplex, inhibiting TORC1 signaling. Leucine binding to SESN1 disrupts this interaction, activating TORC1 signaling. SESN1 is a stress-inducible metabolic regulator potentially protecting against oxidative and genotoxic stress. SESN1 may positively regulate the transcription of genes involved in the oxidative stress response by promoting the SQSTM1-mediated autophagic degradation of KEAP1. It may also prevent reactive oxygen species (ROS) accumulation through its N-terminal domain's alkylhydroperoxide reductase activity. While initially reported to reduce PRDX1 for oxidative stress resistance, this has not been confirmed. SESN1 interacts with the GATOR2 complex, which comprises MIOS, SEC13, SEH1L, WDR24, and WDR59, and this interaction is negatively regulated by leucine. SESN1 also interacts with RRAGA, RRAGB, RRAGC, and RRAGD, potentially acting as a guanine nucleotide dissociation inhibitor for RRAGs and regulating them. SESN1 interacts with KEAP1, RBX1, and SQSTM1 in the SQSTM1-dependent autophagic degradation of KEAP1. It may also interact with PRDX1.
SESN1 is also known as PA26, SEST1.
