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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ATG4B (Autophagin-1) Phosphorylation Modulates Autophagy
Yang, Z., Wilkie-Grantham, R. P., Yanagi, T., Shu, C., Matsuzawa, S., & Reed, J. C. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.658088 · Cited by 96
“Our result, however, seems contradictory to another study, which showed that starvation regulated ATG4B activity through a redox mechanism by which starvation induces ROS, thereby attenuating ATG4B activity and blocking LC3 delipidation (22).”
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From death receptor to reactive oxygen species and c‐Jun N‐terminal protein kinase: the receptor‐interacting protein 1 odyssey
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Androgens Promote Prostate Cancer Cell Growth through Induction of Autophagy
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On the role of autophagy in human diseases: a gender perspective
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TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA
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Hexokinase II inhibitor, 3-BrPA induced autophagy by stimulating ROS formation in human breast cancer cells
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“Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4.”
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Alterations in ROS Activity and Lysosomal pH Account for Distinct Patterns of Macroautophagy in LINCL and JNCL Fibroblasts
Vidal-Donet, J. M., Cárcel‐Trullols, J., Casanova, B., Aguado, C., & Knecht, E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055526 · Cited by 91
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zVAD-induced autophagic cell death requires c-Src-dependent ERK and JNK activation and reactive oxygen species generation
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Autophagy in acute brain injury: Feast, famine, or folly?
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“could postulate that activation of RIP1K signaling increases concentrations of ROS, which activates the autophagic pathway in necrotic cells, as evidence of H202 was found to directly regulate Atg4 (37).”
BackgroundInfluential
Salinomycin Induces Autophagy in Colon and Breast Cancer Cells with Concomitant Generation of Reactive Oxygen Species
Verdoodt, B., Vogt, M., Schmitz, I., Liffers, S., Tannapfel, A., & Mirmohammadsadegh, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044132 · Cited by 95
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Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy
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Autophagy, apoptosis, and mitochondria: molecular integration and physiological relevance in skeletal muscle
Bloemberg, D., & Quadrilatero, J. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00261.2018 · Cited by 100
Regulation of Autophagy by NF-kappaB Transcription Factor and Reactives Oxygen Species
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Oxidative stress as a therapeutic target during muscle wasting: considering the complex interactions
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Erythropoietin Protects Epithelial Cells from Excessive Autophagy and Apoptosis in Experimental Neonatal Necrotizing Enterocolitis
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Background
Omega-3 and -6 fatty acids allocate somatic and germline lipids to ensure fitness during nutrient and oxidative stress in Caenorhabditis elegans
Lynn, D. A., Dalton, H. M., Sowa, J. N., Wang, M. C., Soukas, A. A., & Curran, S. P. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514012112 · Cited by 96
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Autophagy in the Degenerating Human Intervertebral Disc
Gruber, H. E., Hoelscher, G. L., Ingram, J. A., Bethea, S. F., & Hanley, E. N. (2015) · Spine · doi:10.1097/brs.0000000000000865 · Cited by 92
TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease
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Reactive Oxygen Species Regulation of Autophagy in Skeletal Muscles
Rahman, M., Mofarrahi, M., Kristof, A. S., Nkengfac, B., Harel, S., & Hussain, S. N. A. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5410 · Cited by 92
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Influential
Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy
Yeh, C.-H., Hsu, S., Yang, C.-C., Chien, C., & Wang, N.-P. (2009) · Life Sciences · doi:10.1016/j.lfs.2009.11.022 · Cited by 90
PGC‐1α activation as a therapeutic approach in mitochondrial disease
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Stress induced lipid production in Chlorella vulgaris: Relationship with specific intracellular reactive species levels
Menon, K. R., Balan, R., & Suraishkumar, G. K. (2013) · Biotechnology and Bioengineering · doi:10.1002/bit.24835 · Cited by 91
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Tandem Payne/Dakin Reaction: A New Strategy for Hydrogen Peroxide Detection and Molecular Imaging
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Mechanisms of Oxidative Stress and Therapeutic Targets following Intracerebral Hemorrhage
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Cellular Senescence in Age‐Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?
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“Interestingly, it also induces mitophagy, which seems to facilitate bacterial survival by reduction of the level of ROS [220].”
BackgroundInfluential

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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