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Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4
Open accessAbstract
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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“Induction of autophagy following nutrient starvation requires the production of hydrogen peroxide that oxidizes autophagy‐related (ATG)4.”
From Reactive Oxygen Species in Cancer: Current Findings and Future Directions (2021) · cites this paper as [51]
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“MTOR suppression does not always induce autophagy, such as when BECN1 undergoes inhibitory phosphorylation by the growth factor signaling molecules EGFR and AKT, when microglia are activated by lipopolysaccharide (LPS), a TLR4 ligand [766], or during Salmonella infection [767-769].”
From Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1 (2021) · cites this paper as [767]
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“ATG4 is subject to oxidation and subsequent inactivation, which leads to accumulation of LC3-II and increased formation of autophagosomes.(159) Interestingly, increased oxidative/nitrosative stress can inhibit mitophagy by modification and inactivation of Parkin.”
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“0 Ch T Na OC l NC S TM S TB HP DT NB DT NP SN AP 4HN E H 2 O 2 (14) (9) (3) (8) (5) (7) (5) (3) (4) (4)”
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Shpilka, T., Weidberg, H., Pietrokovski, S., & Elazar, Z. (2011) · Genome biology · doi:10.1186/gb-2011-12-7-226 · Cited by 543
“Atg4 regulates a critical step in the autophagic process and is therefore subjected to regulation by reactive oxygen species, for example, which prevent it from reversing the conjugation of Atg8 proteins to PE during autophagy [83].”
BackgroundSelf-citationLoss of iron triggers PINK1/Parkin‐independent mitophagy
Allen, G. F. G., Toth, R., James, J., & Ganley, I. G. (2013) · The EMBO Reports · doi:10.1038/embor.2013.168 · Cited by 555
“ROS are required for starvation-induced autophagy [23] and are produced on mitochondrial damage.”
Oxidative cell death in cancer: mechanisms and therapeutic opportunities
An, X., Yu, W., Liu, J., Tang, D., Li, Y., & Chen, X. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06939-5 · Cited by 617
“Additionally, ROS can directly oxidize and modify key autophagy modulators, such as ATG4, facilitating the formation of autophagosomes [165].”
BackgroundMitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling
Cox, A. G., Winterbourn, C. C., & Hampton, M. B. (2009) · Biochemical Journal · doi:10.1042/bj20091541 · Cited by 550
Calcium and mitochondria in the regulation of cell death
Orrenius, S., Gogvadze, V. G., & Zhivotovsky, B. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.137 · Cited by 546
Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration
Kaarniranta, K., Uusitalo, H. M. T., Błasiak, J., Felszeghy, S., Kannan, R., Kauppinen, A., Salminen, A., Sinha, D., & Ferrington, D. A. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100858 · Cited by 548
“High mitochondrial ROS production, combined with impaired antioxidant systems, results in detrimental protein aggregation (Scherz-Shouval et al., 2007; Korovila et al., 2017).”
Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress
Song, S., Tan, J., Miao, Y., Li, M., & Zhang, Q. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25785 · Cited by 536
“Atg4 is a crucial regulatory component of the autophagosome biogenesis pathway, which is demonstrated by priming newly synthesized Atg8 to enable covalent phosphatidylethanolamine and delipidating Atg8 to facilitate autophagosome-lysosome fusion (Scherz-Shouval et al., 2007).”
BackgroundQuality control of mitochondria: protection against neurodegeneration and ageing
Tatsuta, T., & Langer, T. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601972 · Cited by 525
“Antioxidant treatment suppresses lipidation of Atg8 and autophagosome formation, suggesting that lipid conjugation is a direct consequence of ROS production (Scherz-Shouval et al, 2007).”
BackgroundRegulation of macroautophagy by mTOR and Beclin 1 complexes
Pattingre, S., Espert, L., Biard‐Piechaczyk, M., & Codogno, P. (2007) · Biochimie · doi:10.1016/j.biochi.2007.08.014 · Cited by 535
Interplay between ROS and autophagy in cancer cells, from tumor initiation to cancer therapy
Poillet-Perez, L., Despouy, G., Delage-Mourroux, R., & Boyer-Guittaut, M. (2015) · Redox Biology · doi:10.1016/j.redox.2014.12.003 · Cited by 503
“This oxidization modification mainly inactivates the delipidation activity of ATG4 leading to an increased formation of LC3-associated autophagosomes [20] (Fig.”
BackgroundReactive Oxygen Species in the Tumor Microenvironment: An Overview
Weinberg, F., Ramnath, N., & Nagrath, D. (2019) · Cancers · doi:10.3390/cancers11081191 · Cited by 502
Autophagy in the liver: functions in health and disease
Ueno, T., & Komatsu, M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.185 · Cited by 500
Overview of macroautophagy regulation in mammalian cells
Mehrpour, M., Esclatine, A., Beau, I., & Codogno, P. (2010) · Cell Research · doi:10.1038/cr.2010.82 · Cited by 516
Khan, M. I., Mohammad, A., Patil, G., Naqvi, S. A. H., Chauhan, L. K. S., & Ahmad, I. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.10.080 · Cited by 491
“Our observations and conclusion on autophagy and cell death due to mitochondrial collapse are well supported by a couple of previous studies [54,55].”
ResultOrchestrating Redox Signaling Networks through Regulatory Cysteine Switches
Paulsen, C. E., & Carroll, K. S. (2009) · ACS Chemical Biology · doi:10.1021/cb900258z · Cited by 487
“ing a disulfide bond involving the catalytic cysteine (74).”
BackgroundAutophagy in cancer metastasis
Mowers, E. E., Sharifi, M. N., & Macleod, K. F. (2016) · Oncogene · doi:10.1038/onc.2016.333 · Cited by 487
“Elevated ROS induced by matrix detachment also likely contributes to autophagy induction via activation of Atg4 directly (79).”
Complex interplay between autophagy and oxidative stress in the development of pulmonary disease
Ornatowski, W., Lü, Q., Yegambaram, M., Flores, A. G., Zemskov, E. A., Maltepe, E., Fineman, J. R., Wang, T., & Black, S. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101679 · Cited by 484
“Increased generation of mitochondrial H2O2 oxidizes and inactivates a critical cysteine residue (Cys78) on ATG4 catalytic site [123].”
BackgroundHigh-Mobility Group Box 1, Oxidative Stress, and Disease
Tang, D., Kang, R., Zeh, H. J., & Lotze, M. T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3356 · Cited by 475
“Indeed, many stimuli that induce ROS generation also induce autophagy, including nutrient starvation, mitochondrial toxins, and hypoxia (193).”
BackgroundMitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner
Frank, M., Duvezin-Caubet, S., Koob, S., Occhipinti, A., Jagasia, R., Petcherski, A., Ruonala, M. O., Priault, M., Salin, B., & Reichert, A. S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.08.007 · Cited by 468
“1A), a condition known to increase cellular ROS levels grossly [31,32].”
BackgroundThe Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment
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Biogenesis and Cargo Selectivity of Autophagosomes
Weidberg, H., Shvets, E., & Elazar, Z. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-052709-094552 · Cited by 466
Self-citationMitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases
Giorgi, C., Marchi, S., Simões, I. C. M., Ren, Z., Morciano, G., Perrone, M., Patalas‐Krawczyk, P., Borchard, S., Jędrak, P., Pierzynowska, K., et al. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.006 · Cited by 484
Crosstalk between Oxidative Stress and SIRT1: Impact on the Aging Process
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“[147] demonstrated that ROS oxidized the Cys77 and”
BackgroundOxidative Stress, Redox Signaling, and Autophagy: Cell Death Versus Survival
Navarro-Yepes, J., Burns, M., Anandhan, A., Khalimonchuk, O., Razo, L. M. D., Quintanilla‐Vega, B., Pappa, A., Panayiotidis, M. I., & Franco, R. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5837 · Cited by 467
“Recently, it was demonstrated that upon starvation, increased generation of mitochondrial H 2 O 2 oxidizes and inactivates Atg4 after the initial cleavage of LC3, ensuring the structural integrity of the mature (128) (Fig.”
Cysteine/cystine redox signaling in cardiovascular disease
Go, Y.-M., & Jones, D. P. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.11.029 · Cited by 447
“For instance, the cysteine protease Atg4 is regulated by a redoxdependent mechanism during starvation-induced autophagy [46].”
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“Under nutrient-starvation conditions, ROS is increased, contributing to autophagy (Scherz-Shouval et al., 2007).”
BackgroundMolecular machinery and interplay of apoptosis and autophagy in coronary heart disease
Dong, Y., Chen, H., Gao, J., Liu, Y., Li, J., & Wang, J. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.09.001 · Cited by 444
Gómez-Virgilio, L., Silva-Lucero, M.-D.-C., Flores-Morelos, D.-S., Gallardo-Nieto, J., Lopez-Toledo, G., Abarca-Fernandez, A.-M., Zacapala-Gómez, A.-E., Luna-Muñoz, J., Montiel-Sosa, F., Soto-Rojas, L. O., et al. (2022) · Cells · doi:10.3390/cells11152262 · Cited by 431
“Finally, redox processes mediate changes in ATG4, thereby regulating the formation of autophagosomes [93,94].”
BackgroundActivation of Autophagy Protects Against Acetaminophen–Induced Hepatotoxicity
Ni, H., Bockus, A. B., Boggess, N., Jaeschke, H., & Ding, W. (2011) · Hepatology · doi:10.1002/hep.24690 · Cited by 429
“ROS can modulate Atg4B activity by directly oxidizing a specific cysteine residue, Cys81, on Atg4B.(30) It remains to be studied how exactly NAC suppresses APAP-induced autophagy.”
BackgroundATM functions at the peroxisome to induce pexophagy in response to ROS
Zhang, J., Tripathi, D. N., Ji, J., Alexander, A., Kim, J., Powell, R. T., Dere, R., Tait-Mulder, J., Lee, J., Paull, T. T., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3230 · Cited by 442
“3 independent experiments, 100 cells analyzed in each experiment independent experiments yes % ATM cytosolic localization: ATM WT control (10, 12, 12); ATM WT H2O2 (19, 19, 23); ATM RQ control (8, 5, 4); ATM RQ H2O2 (6, 7, 5) Figure 3b 2 independent experiemnts independent experiments Fold change in ROS: Control defin…”
Method
Metadata
- Authors
- Scherz‐Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., & Elazar, Z.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Elazar, Zvulun
- Venue
- The EMBO Journal
- Published
- 2007-03-08
- Volume
- 26
- Issue
- 7
- Pages
- 1749-1760
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- 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
- Open access
- bronze
- doi.org
- Licence
- 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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