Sestrin2 is induced by glucose starvation via the unfolded protein response and protects cells from non-canonical necroptotic cell death.

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.

• Authors: Boxiao Ding, Anita Parmigiani, Ajit S Divakaruni, Kellie Archer, Anne N Murphy, Andrei V Budanov
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 22538 (Mar 02 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26932729 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Atf4 protein, mouse
• Multiprotein Complexes
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Nuclear Proteins
• Reactive Oxygen Species
• Activating Transcription Factor 4
• Peroxidases
• Sesn2 protein, mouse
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Activating Transcription Factor 4 (physiology)
• Animals
• Apoptosis (physiology)
• Endoplasmic Reticulum Stress (physiology)
• Glucose (metabolism)
• Mechanistic Target of Rapamycin Complex 1
• Mice
• Mice, Knockout
• Multiprotein Complexes (metabolism)
• NF-E2-Related Factor 2 (physiology)
• Nuclear Proteins (biosynthesis, physiology)
• Peroxidases
• Reactive Oxygen Species (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Unfolded Protein Response