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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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BackgroundChompoosor, A., Saha, K., Ghosh, P. S., Macarthy, D. J., Miranda, O. R., Zhu, Z., Arcaro, K. F., & Rotello, V. M. (2010) · Small · doi:10.1002/smll.201000463 · Cited by 275
Autophagy proteins control goblet cell function by potentiating reactive oxygen species production
Patel, K., Miyoshi, H., Beatty, W. L., Head, R. D., Malvin, N. P., Cadwell, K., Guan, J., Saitoh, T., Akira, S., Seglen, P. O., et al. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.233 · Cited by 287
“Additionally, intracellular ROS can regulate autophagy by altering Atg4 activity (Scherz-Shouval et al , 2007).”
LC3-Associated Phagocytosis and Inflammation
Heckmann, B. L., Boada-Romero, E., Cunha, L. D., Magne, J., & Green, D. R. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.08.012 · Cited by 276
“following induction by different stimuli as reported previously [71], and interestingly, the delipidation activity of ATG4 is inhibited by ROS [72], extending the presence of LC3 proteins in the autophagosomal membrane and favoring autophagy.”
Regulation of the aging process by autophagy.
Salminen, A., & Kaarniranta, K. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.03.004 · Cited by 270
Oxidative stress and the role of redox signalling in chronic kidney disease
Kishi, S., Nagasu, H., Kidokoro, K., & Kashihara, N. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00775-0 · Cited by 297
“The cysteine protease HsAtg4 is also a direct target of oxidation by H 2 O 2 , and the presence of HsAtg4 is essential for autophagosome formation 23,29 .”
Reactive Oxygen Species and Autophagy in Plants and Algae
Pérez‐Pérez, M. E., Lemaire, S. D., & Crespo, J. L. (2012) · PLANT PHYSIOLOGY · doi:10.1104/pp.112.199992 · Cited by 269
Autophagy During Cardiac Stress: Joys and Frustrations of Autophagy
Gottlieb, R. A., & Mentzer, R. M. (2010) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021909-135757 · Cited by 270
“Atg4 is redox regulated and appears to be responsible for upregulating autophagy in the face of oxidative stress (2).”
BackgroundDing, Y., Kim, S. L., Lee, S.-Y., Koo, J. K., Wang, Z., & Choi, M. E. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013101068 · Cited by 264
Yuan, H., Perry, C. N., Huang, C., Iwai‐Kanai, E., Carreira, R., Glembotski, C. C., & Gottlieb, R. A. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01051.2008 · Cited by 265
How to Live Long and Prosper: Autophagy, Mitochondria, and Aging
Yen, W.-L., & Klionsky, D. J. (2008) · Physiology · doi:10.1152/physiol.00013.2008 · Cited by 271
“Oxidation of this protein leads to inhibition of its deconjugation activity (168), which allows the accumulation of phosphatidylethanolamine-conjugated Atg8 on the autophagosome membrane, an important step in autophagosome formation (204).”
BackgroundInfluentialDehdashtian, E., Mehrzadi, S., Yousefi, B., Hosseinzadeh, A., Reiter, R. J., Safa, M., Ghaznavi, H., & Naseripour, M. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.12.001 · Cited by 267
“5) through mTOR inhibition, increase in Beclin1 expression, and LC3-I to LC3-II conversion (94-97).”
BackgroundHallmarks of Aging: An Autophagic Perspective
Barbosa, M. C., Grosso, R. A., & Fader, C. M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00790 · Cited by 275
“Mitochondrial ROS can activate the autophagic pathway upon starvation by the activation of ATG4 (41), and this in turn leads to autophagic degradation of mitochondria (mitophagy) in order to reduce the ROS levels by limiting the number of mitochondria per cell (42).”
BackgroundWong, C. H., Iskandar, K. B., Yadav, S. K., Hirpara, J. L., Loh, T. K. S., & Pervaiz, S. (2010) · PLoS ONE · doi:10.1371/journal.pone.0009996 · Cited by 263
“Indeed, H2O2 was also found to be an important mediator in starvation-induced autophagy, through its activity in regulating Atg4 protease[20].”
Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway
Gurusamy, N., Lekli, I., Mukherjee, S., Ray, D., Ahsan, M. K., Gherghiceanu, M., Popescu, L. M., & Das, D. K. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp384 · Cited by 267
“Recently, autophagy has been found to be regulated by redox signalling.(11,12) As resveratrol, a polyphenolic phytoalexin found in grapes, wines, peanuts, and several other fruits and vegetables, has been found to precondition the ischaemic myocardium by redox signalling,(13) we used this compound to explore the mecha…”
BackgroundThe Atg8 family: multifunctional ubiquitin-like key regulators of autophagy
Rawet-Slobodkin, M., & Elazar, Z. (2013) · Essays in Biochemistry · doi:10.1042/bse0550051 · Cited by 259
Self-citationMitochondrial ROS Formation in the Pathogenesis of Diabetic Cardiomyopathy
Kaludercic, N., & Lisa, F. D. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00012 · Cited by 268
“Mitochondrial ROS are implicated in the activation of the canonical autophagy (178), but on the other hand excessive mitochondrial ROS formation impairs lysosomal biogenesis, function and the autophagy process in the cardiac myocytes (156, 168).”
BackgroundRecent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies
Mueller, A., Payandeh, Z., Mohammadkhani, N., Mubarak, S. M. H., Zakeri, A., Bahrami, A. A., Brockmueller, A., & Shakibaei, M. (2021) · Cells · doi:10.3390/cells10113017 · Cited by 283
“Since ROS have been demonstrated to be involved in the formation of autophagosomes, ROS-mediated induction of autophagy might be pivotal in the resistance of synovial and peripheral RA T-cells against apoptosis and the production of citrullinated peptides in APCs [153].”
BackgroundBetin, V. M. S., & Lane, J. D. (2009) · Journal of Cell Science · doi:10.1242/jcs.046250 · Cited by 261
“The C54 endopeptidase, Atg4, is a crucial regulatory component of the autophagosome biogenesis pathway (Scherz-Shouval et al., 2007): it cleaves the C-terminus of newly synthesised Atg8 to reveal a glycine residue (priming) required for covalent attachment to PE (lipidation), and later removes PE from outer-membrane-b…”
InfluentialZhang, J., Kim, J., Alexander, A., Cai, S., Tripathi, D. N., Dere, R., Tee, A. R., Tait-Mulder, J., Di Nardo, A., Han, J. M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2822 · Cited by 258
“As a major site of ROS generation, we hypothesized TSC at the peroxisome might induce autophagy, which is regulated by both mTORC1 6–8, 11 and ROS 27, 28 .”
Ferraro, E., Giammarioli, A. M., Chiandotto, S., Spoletini, I., & Rosano, G. M. C. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5773 · Cited by 275
“The mechanism through which ROS induce autophagy has not been fully elucidated, but it is believed that ROS could increase Beclin1 expression and/or regulate the activity of Atg4 (27, 28, 165).”
BackgroundInfluentialHuman IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria
Singh, S., Ornatowski, W., Vergne, I., Naylor, J., Delgado, M. A., Roberts, E. A., Ponpuak, M., Master, S. S., Pilli, M., White, E., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2119 · Cited by 268
“, whereas ROS generated by mitochondria induce autophagy through Atg4 (ref”
BackgroundKeap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy
Fan, W., Tang, Z., Chen, D., Moughon, D., Ding, X., Chen, S., Zhu, M., & Zhong, Q. (2010) · Autophagy · doi:10.4161/auto.6.5.12189 · Cited by 251
“It has been suggested that oxidative stress might oxidize Atg4 at Cysteine residues to regulate LC3 processing.(36) Here, we provide strong the size of these puncta did not undergo any dramatic change upon CQ treatment (Fig.”
BackgroundMitochondrial morphology in mitophagy and macroautophagy
Gomes, L. C., & Scorrano, L. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.02.012 · Cited by 259
“hagy [128].”
ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy
Rodríguez-Vargas, J. M., Ruiz-Magaña, M. J., Ruiz‐Ruiz, C., Majuelos‐Melguizo, J., Peralta-Leal, A., Rodríguez, M. I., Muñoz‐Gámez, J. A., de Almodóvar, M. R., Siles, E., López‐Rivas, A., et al. (2012) · Cell Research · doi:10.1038/cr.2012.70 · Cited by 256
Mitochondrial dysfunction and mitophagy: the beginning and end to diabetic nephropathy?
Higgins, G. C., & Coughlan, M. T. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12503 · Cited by 257
“It can be further postulated that this excess ROS may stimulate mitophagy activity in the kidney and regulate the turnover of damaged mitochondria (Chen et al., 2007; Scherz-Shouval et al., 2007; Bensaad et al., 2009).”
BackgroundYao, H., & Rahman, I. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.10.022 · Cited by 254
“It has been shown that accumulation of ROS led to autophagy to overcome oxidative stress (Scherz-Shouval et al., 2007a; Scherz-Shouval et al., 2007b).”
BackgroundGlutathione Efflux and Cell Death
Franco, R., & Cidlowski, J. A. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4553 · Cited by 254
Oxidative Stress and Autophagy in Cardiac Disease, Neurological Disorders, Aging and Cancer
Essick, E. E., & Sam, F. (2010) · Oxidative Medicine and Cellular Longevity · doi:10.4161/oxim.3.3.12106 · Cited by 251
Autophagy in age-related macular degeneration
Kaarniranta, K., Błasiak, J., Liton, P. B., Boulton, M. E., Klionsky, D. J., & Sinha, D. (2022) · Autophagy · doi:10.1080/15548627.2022.2069437 · Cited by 250
“Reactive oxygen species (ROS) have been described to be involved in nutrient-starvation-induced autophagy as signaling molecules [17].”
BackgroundLi, M., Hou, Y., Wang, J., Chen, X., Shao, Z.-M., & Yin, X. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.199059 · Cited by 250
miR-376b controls starvation and mTOR inhibition-related autophagy by targeting ATG4C and BECN1
Korkmaz, G., le Sage, C., Tekirdağ, K. A., Agami, R., & Gözüaçık, D. (2012) · Autophagy · doi:10.4161/auto.8.2.18351 · Cited by 252
“The other target, ATG4C, has been shown to function in autophagic membrane elongation through its effects on the maturation of LC3 proteins.(18,19,22,23) ATG4B rather than ATG4C was responsible for LC3 protein delipidation, an event important for autophagosome/late endosome-lysosome fusion and LC3 protein recycling.”
BackgroundThe glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications
Xiao, D., Zeng, L., Kang, Y., Kong, X., Wu, G., & Yin, Y. (2016) · Amino Acids · doi:10.1007/s00726-016-2254-8 · Cited by 246
“ROS is mainly derived from the mitochondrial respiratory chain and initiates autophagy in a manner that is sensitive to amino acids (Scherz-Shouval et al. 2007; Murphy 2009).”
BackgroundThe many roles of NOX2 NADPH oxidase-derived ROS in immunity
Lam, G. Y., Huang, J., & Brumell, J. H. (2010) · Seminars in Immunopathology · doi:10.1007/s00281-010-0221-0 · Cited by 251
“Furthermore, in MEFs with and without Atg5, an essential autophagy component, no difference in the ROS levels was observed [151].”
Background
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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