Abstract
Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that UPR induces Sestrin2 via ATF4 and NRF2 transcription factors and demonstrate that Sestrin2 protects cells from glucose starvation-induced cell death. Sestrin2 inactivation sensitizes cells to necroptotic cell death that is associated with a decline in ATP levels and can be suppressed by Necrostatin 7. We propose that Sestrin2 protects cells from glucose starvation-induced cell death via regulation of mitochondrial homeostasis.
Highlights
The data represent a mean of three independent experiments ± S.D
The outcome of unfolded protein response (UPR) activation depends on the severity and duration of endoplasmic reticulum (ER) stress: while the acute response potentially mitigates the consequences of ER stress, prolonged ER stress eventually stimulates cell death[4,5]
SESN2 has recently been reported as a protein activated by ER stress via ATF4, among the other potential UPR transcriptional factors[26,40]
Summary
We demonstrated that protein products of Sestrin genes work as antioxidant proteins suppressing oxidative DNA damage and mutagenesis[12,13]. Sestrins inhibit mammalian target of rapamycin (mTOR) complex 1 (mTORC1) kinase, a critical regulator of cell growth and metabolism[14,15,16]. Sestrins inhibit mTORC1 in a manner dependent on AMPK and tuberous sclerosis complex (TSC), which, in turn, inhibits the small GTPase Rheb, a critical activator of mTORC114,15,17–19. We demonstrated that SESN2 is activated in response to some metabolic stress factors and is involved in the regulation of cell viability[9,24]; the precise role of SESN2 in the regulation of cell death is not well established. We show that glucose starvation stimulates SESN2 via induction of ER stress and that SESN2 protects cells from necrotic cell death through the support of cell metabolism, ATP production and mitochondrial function
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
