Abstract:
:The denitrosylase S-nitrosoglutathione reductase (GSNOR) has been suggested to sustain mitochondrial removal by autophagy (mitophagy), functionally linking S-nitrosylation to cell senescence and aging. In this study, we provide evidence that GSNOR is induced at the translational level in response to hydrogen peroxide and mitochondrial ROS. The use of selective pharmacological inhibitors and siRNA demonstrates that GSNOR induction is an event downstream of the redox-mediated activation of ATM, which in turn phosphorylates and activates CHK2 and p53 as intermediate players of this signaling cascade. The modulation of ATM/GSNOR axis, or the expression of a redox-insensitive ATM mutant influences cell sensitivity to nitrosative and oxidative stress, impairs mitophagy and affects cell survival. Remarkably, this interplay modulates T-cell activation, supporting the conclusion that GSNOR is a key molecular effector of the antioxidant function of ATM and providing new clues to comprehend the pleiotropic effects of ATM in the context of immune function.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Cirotti C,Rizza S,Giglio P,Poerio N,Allega MF,Claps G,Pecorari C,Lee JH,Benassi B,Barilà D,Robert C,Stamler JS,Cecconi F,Fraziano M,Paull TT,Filomeni Gdoi
10.15252/embr.202050500subject
Has Abstractpub_date
2020-11-27 00:00:00pages
e50500eissn
1469-221Xissn
1469-3178pub_type
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