Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress.
ATM
GSNOR
ROS
T cell
mitophagy
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
24
03
2020
revised:
01
10
2020
accepted:
14
10
2020
pubmed:
28
11
2020
medline:
1
6
2021
entrez:
27
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33245190
doi: 10.15252/embr.202050500
pmc: PMC7788447
doi:
Substances chimiques
Aldehyde Oxidoreductases
EC 1.2.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e50500Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL128192
Pays : United States
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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