Cited by 2,101Autophagy in Disease and TherapyRedox biology and oxidative stressUbiquitin and proteasome pathways

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Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4

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Scherz‐Shouval, Ruth, Shvets, Elena, Fass, Ephraim, Shorer, Hagai, Gil, Lidor, Elazar, Zvulun·2007·The EMBO Journal

DOI 10.1038/sj.emboj.7601623PMC PMC6517991

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Abstract

Autophagy is a major catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles. This pathway is activated under environmental stress conditions, during development and in various pathological situations. In this study, we describe the role of reactive oxygen species (ROS) as signaling molecules in starvation-induced autophagy. We show that starvation stimulates formation of ROS, specifically H(2)O(2). These oxidative conditions are essential for autophagy, as treatment with antioxidative agents abolished the formation of autophagosomes and the consequent degradation of proteins. Furthermore, we identify the cysteine protease HsAtg4 as a direct target for oxidation by H(2)O(2), and specify a cysteine residue located near the HsAtg4 catalytic site as a critical for this regulation. Expression of this regulatory mutant prevented the formation of autophagosomes in cells, thus providing a molecular mechanism for redox regulation of the autophagic process.

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1 retracted

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“These data are consistent with several reports indicating ROS as an upstream signaling molecule for survival in the activation of autophagy (Scherz-Shouval et al., 2007; Marino et al., 2010).”
Result
The role of ion disequilibrium in induction of root cell death and autophagy by environmental stresses
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“, 2009), hypoxia/ROS exposure (Chen et al., 2009; Scherz-Shouval et al., 2007) or intra-”
Background
Autophagy and Crohn's Disease: At the Crossroads of Infection,Inflammation, Immunity, and Cancer
Brest, P., Corcelle–Termeau, E., Césaro, A., Chargui, A., Belaïd, A., Klionsky, D. J., Vouret‐Craviari, V., Hébuterne, X., Hofman, P. M., & Mograbi, B. (2010) · Current Molecular Medicine · doi:10.2174/156652410791608252 · Cited by 85
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“However, high levels of oxidants are responsible for the inactivity of Atg5, beclin-1, and other autophagy-associated proteins [12, 14, 34].”
Background
The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms
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“There is a growing body of evidence showing that autophagy is activated by ROS as a cytoprotective process in which ROS production is increased and is required for induction of autophagy under starvation conditions (93).”
Background
High Glucose Condition Induces Autophagy in Endothelial Progenitor Cells Contributing to Angiogenic Impairment
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“Autophagy can be induced by ROS through direct modiﬁcation of key proteins involved in the autophagy process, including Atg4, Atg5, and Beclin-1, and indirect alteration of signaling pathway molecules including JNK and p38 [106, 107].”
Background
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Tiwari, M., Sharma, L. K., Vanegas, D., Callaway, D. A., Bai, Y., Lechleiter, J. D., & Herman, B. A. (2014) · Autophagy · doi:10.4161/auto.28528 · Cited by 78
Inhibition of Integrin-mediated Crosstalk with Epidermal Growth Factor Receptor/Erk or Src Signaling Pathways in Autophagic Prostate Epithelial Cells Induces Caspase-independent Death
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“Interestingly, a recent report indicates that high levels of ROS are required for starvation-induced autophagy ( Scherz-Shouval et al., 2007 ).”
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Calyxin Y induces hydrogen peroxide-dependent autophagy and apoptosis via JNK activation in human non-small cell lung cancer NCI-H460 cells
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“In short, an increase in intracellular H2O2 as well as activation of MAPK all participate the autophagic execution [18].”
Background
Ameliorative effects of selenium on arsenic-induced cytotoxicity in PC12 cells via modulating autophagy/apoptosis
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“(3) Elongation: ROS produced upon settings of nutrient scarcity are required for the oxidation of a cysteine residue within the catalytic domain of ATG4, which performs the enzymatic cleavage of LC3 [62].”
Background
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“Similar results were obtained in HEK293T and Hela cells, in which an increase in autophagic activity was linked to enhanced levels of superoxide radicals [44,45].”
Result
Lysosomal thiol reductase negatively regulates autophagy by altering glutathione synthesis and oxidation
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Autophagy and KRT8/keratin 8 protect degeneration of retinal pigment epithelium under oxidative stress
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“related disorders is caused partly as the autophagic pathways become less efficient with age.(12) The levels of proteins related”
Background
Autophagy: A New Mechanism of Prosurvival and Drug Resistance in Multiple Myeloma
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“[67] have demonstrated that stress conditions and amino acids deprivation induce the formation of PI3KC3/Beclin-1 complex that stimulates the mitochondria to accumulate H2O2, subsequently secreted into the cytosol.”
Background
Viral interactions with macroautophagy: A double-edged sword
Lin, L., Dawson, P. W. H., & Richardson, C. D. (2010) · Virology · doi:10.1016/j.virol.2010.03.026 · Cited by 74
“…2007), increases in reactive oxygen species (ROS) (Djavaheri-Mergny et al., 2007; Djavaheri-Mergny et al., 2006; Scherz-Shouval and Elazar, 2007; Scherz-Shouval et al., 2007), and endoplasmic reticulum (ER) stress (Ding et al., 2007; Kouroku et al., 2007; Ogata et al., 2006; Yorimitsu et al.,…”
Background
Understanding the non-canonical pathways involved in p53-mediated tumor suppression
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“Interestingly, a link between ROS and the induction of autophagy has recently been revealed (47).”
Background
The activation of c-Jun NH2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells
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“Furthermore, several recent reports indicated that reactive oxygen species (ROS) induced autophagy in response to chemotherapy [17,18].”
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“ATG4 thiol modification at Cys81 decreases its activity by suppressing LC3 delipidation (Scherz-Shouval et al. 2007).”
Background
CXCR4-mediated signaling regulates autophagy and influences acute myeloid leukemia cell survival and drug resistance
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“The delipidation also likely involves Atg4, the same enzyme involved in Atg8→ Atg4 (LC3-I) conversion (Scherz-Shouval et al., 2007; Fernandez and Lopez-Otin, 2015).”
Background
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“, deprivation of growth factors/nutrients, inhibition of proteasome, inhibition of receptor tyrosine kinases/Akt/mammalian target of rapamycin (mTOR) signaling, and unbalance of ROS homeostasis) and is characterized by a cascade of events including degradation of cytoplasmic proteins or entire organelles [36,52,53].”
Background
Understanding the Role of Autophagy in Cancer Formation and Progression Is a Real Opportunity to Treat and Cure Human Cancers
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“ROS also have an important role in the induction of autophagy through modification of proteins such as Atg4, stimulating recruitment of LC3 to autophagosomal membranes (Scherz-Shouval et al., 2007).”
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“Oxidized ATG4 loses its delipidation ability for LC3, thereby increasing LC3 lipidation for autophagosome formation and autophagy induction [106].”
Background
Reactive Oxygen Species Across Death Pathways: Gatekeepers of Apoptosis, Ferroptosis, Pyroptosis, Paraptosis, and Beyond
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Glutamate dehydrogenase contributes to leucine sensing in the regulation of autophagy
Lorin, S., Tol, M. J., Bauvy, C., Strijland, A., Poüs, C., Verhoeven, A. J., Codogno, P., & Meijer, A. J. (2013) · Autophagy · doi:10.4161/auto.24083 · Cited by 79

Authors: Scherz‐Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z.
Affiliations: Weizmann Institute of Science (IL)
Corresponding author: Elazar, Zvulun
ORCID: Scherz‐Shouval, Ruth
Elazar, Zvulun
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2007-03-08
Volume: 26
Issue: 7
Pages: 1749-1760
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/sj.emboj.7601623
PMC: PMC6517991
OpenAlex: W2114806766
Cited by: 2,101
References: 51
Citations by year: 2026: 38 · 2025: 60 · 2024: 77 · 2023: 86 · 2022: 115 · 2021: 141 · 2020: 137 · 2019: 108 · 2018: 122 · 2017: 136 · 2016: 118 · 2015: 132 · 2014: 170 · 2013: 140 · 2012: 146
FWCI: 59.86
Type: journal article
Language: en
Update notices: correction (2019-05-15)
erratum (2019-05-15)
Open access: bronze
doi.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Israel Science Foundation
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: reactive oxygen species, autophagy, ATG4, hydrogen peroxide, starvation, redox regulation, cysteine protease, autophagosome formation, oxidative stress signaling, protein degradation
MeSH terms: Autophagy-Related Proteins, Amino Acid Sequence, Animals, Autophagy, Cricetulus, Cysteine, Cysteine Endopeptidases, Enzyme Activation, Food Deprivation, Cricetinae, HeLa Cells, Humans, Models, Biological, Molecular Sequence Data, Mutation, Oxidation-Reduction, Phylogeny, CHO Cells, Reactive Oxygen Species, Phosphatidylinositol 3-Kinases, Mice

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Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4

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