Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress
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- embr.202050500
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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.
Originalsprog | Engelsk |
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Artikelnummer | e50500 |
Tidsskrift | EMBO Reports |
Vol/bind | 22 |
Udgave nummer | 1 |
ISSN | 1469-221X |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
The authors are grateful to Laila Fisher for secretarial work. This work has been supported by grants from the Novo Nordisk Foundation (2018-0052550 to G.F); Danish Cancer Society (KBVU R146-A9414 and R231-A13855 to G.F.; KBVU R146-A9364; and R231-A14034 to F.C.); the Italian Association for Cancer Research, (IG2016-19069 to D.B. and IG2017-20719 to G.F.); Italian Ministry of University and Research (MIUR-JPI-HDHL-NUTRICOG-MiTyrAge and PRIN-2015LZE9944 to D.B); and Italian Ministry of Health (RF-2016-02362022 to D.B.). Chiara Pecorari is recipient of a PhD fellowship from Danish Cancer Research Foundation (Dansk Kraeftforskningsfond, DKF-0-0-532). Giuseppina Claps was supported by the Marie Curie, Campus France Fellowship - PRESTIGE-2017-3-0017. Moreover, laboratory in Copenhagen is part of the Center of Excellence in Autophagy, Recycling and Disease (CARD), funded by the Danish National Research Foundation (DNRF125).
Funding Information:
The authors are grateful to Laila Fisher for secretarial work. This work has been supported by grants from the Novo Nordisk Foundation (2018‐0052550 to G.F); Danish Cancer Society (KBVU R146‐A9414 and R231‐A13855 to G.F.; KBVU R146‐A9364; and R231‐A14034 to F.C.); the Italian Association for Cancer Research, (IG2016‐19069 to D.B. and IG2017‐20719 to G.F.); Italian Ministry of University and Research (MIUR‐JPI‐HDHL‐NUTRICOG‐MiTyrAge and PRIN‐2015LZE9944 to D.B); and Italian Ministry of Health (RF‐2016‐02362022 to D.B.). Chiara Pecorari is recipient of a PhD fellowship from Danish Cancer Research Foundation (Dansk Kraeftforskningsfond, DKF‐0‐0‐532). Giuseppina Claps was supported by the Marie Curie, Campus France Fellowship ‐ PRESTIGE‐2017‐3‐0017. Moreover, laboratory in Copenhagen is part of the Center of Excellence in Autophagy, Recycling and Disease (CARD), funded by the Danish National Research Foundation (DNRF125).
Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
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