Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress

被引：42

作者：

Cirotti C. ^{[1
,2
]}

Rizza S. ^{[3
]}

Giglio P. ^{[1
]}

Poerio N. ^{[1
]}

Allega M.F. ^{[3
,13
]}

Claps G. ^{[4
]}

Pecorari C. ^{[3
]}

Lee J.-H. ^{[5
]}

Benassi B. ^{[6
]}

Barilà D. ^{[1
,2
]}

Robert C. ^{[4
,7
,8
]}

Stamler J.S. ^{[9
]}

Cecconi F. ^{[1
,10
,11
]}

Fraziano M. ^{[1
]}

Paull T.T. ^{[5
]}

Filomeni G. ^{[1
,3
,12
]}

机构：

[1] Department of Biology, Tor Vergata University, Rome

[2] Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome

[3] Redox Signaling and Oxidative Stress Group, Danish Cancer Society Research Center, Copenhagen

[4] INSERM, U981, Villejuif

[5] Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX

[6] Division of Health Protection Technologies, ENEA-Casaccia, Rome

[7] Université Paris Sud, Université Paris-Saclay, Kremlin-Bicêtre

[8] Oncology Department, Gustave Roussy, Université Paris-Saclay, Villejuif

[9] Institute for Transformative Molecular Medicine, Case Western Reserve University and Harrington Discovery Institute, University Hospitals Case Medical Center, Cleveland, OH

[10] Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen

[11] Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome

[12] Center for Healthy Aging, Copenhagen University, Copenhagen

[13] Cancer Research UK Beatson Institute, Garscube Estate, Glasgow

来源：

The EMBO Reports | 2021年 / 22卷 / 1期

关键词：

ATM; GSNOR; mitophagy; ROS; T cell;

D O I：

10.15252/embr.202050500

中图分类号：

学科分类号：

摘要：

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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license

引用

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