Sestrin (SESN) (SESN)

Sestrins are a family of highly conserved, stress-inducible proteins (SESN1, SESN2, and SESN3) that play a pivotal role in maintaining metabolic homeostasis and protecting cells against oxidative stress (Budanov et al., 2004). They function as critical negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) by acting as leucine sensors; when leucine is low, Sestrins bind and inhibit GATOR2, thereby preventing mTORC1 activation (Wolfson et al., 2016). Additionally, Sestrins promote the activation of AMP-activated protein kinase (AMPK) and facilitate the regeneration of overoxidized peroxiredoxins, contributing to antioxidant defense (Lee et al., 2010). Due to their involvement in aging, obesity, and insulin resistance, Sestrins are emerging as significant therapeutic targets for age-related and metabolic diseases (Kim et al., 2020). Pharmacological modulation of Sestrin activity, particularly SESN2, is being explored to mimic the beneficial effects of exercise and dietary restriction, with compounds like NV-5138 currently under investigation for conditions such as treatment-resistant depression (Kato et al., 2019).

Other names

SESN1SESN2SESN3PA26Hi95Sestrin 1Sestrin 2Sestrin 3

Sestrins function as leucine sensors that negatively regulate mTORC1 by binding to GATOR2 in the absence of leucine (Wolfson et al., 2016). They also activate AMPK and support antioxidant defenses by regenerating overoxidized peroxiredoxins (Budanov et al., 2004; Lee et al., 2010).