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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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“Intriguingly, oxidative stress is a potent regulator of autophagy (Scherz-Shouval et al., 2007; Huang et al., 2011; Scherz-Shouval and Elazar, 2011), suggesting the potential for functional interactions between the lysosomal and mitochondrial pathways.”
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“In addition, under starvation or stress conditions, ROS accumulation is essential for the induction of autophagy (Scherz-Shouval et al., 2007).”
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“It has been reported that the first step of the processing is very fast and even a small amount of ATG4B is sufficient for this natural processing work [42].”
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“Following the phagophore formation, Atg8 is cleaved by Atg4 (the cleaved Atg8 is also known as LC3-I), and then transferred to Atg3 by Atg7.”
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BackgroundThe crosstalk of NAD, ROS and autophagy in cellular health and ageing
Sedlackova, L., & Korolchuk, V. I. (2020) · Biogerontology · doi:10.1007/s10522-020-09864-0 · Cited by 48
“In human cells, the hydrolysing (deconjugating) activity of ATG4B is inhibited by the oxidation of one of two Cys residues (Cys74 or Cys78) and leads to improved stability of LC3–PE and increased formation of autophagosomes (Scherz-Shouval et al. 2007).”
BackgroundCoenzyme Q redox signalling and longevity
Scialò, F., & Sanz, A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.018 · Cited by 48
Zhang, K., Huang, Q., Li, X., Zhao, Z., Hong, C., Sun, Z., Deng, B., Li, C., Zhang, J., & Wang, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1352479 · Cited by 49
Serviddio, G., Romano, A. D., Cassano, T., Bellanti, F., Altomare, E., & Vendemiale, G. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211796904740 · Cited by 45
“[127] Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z.”
BackgroundA systems biology viewpoint on autophagy in health and disease
Huett, A. S., Goel, G., & Xavier, R. J. (2010) · Current Opinion in Gastroenterology · doi:10.1097/mog.0b013e32833ae2ed · Cited by 47
José, C., Melser, S., Bénard, G., & Rossignol, R. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4357 · Cited by 51
“Mitophagy may be induced to clear cells of damaged mitochondria as is the case when bio-energetics become substantially impaired (215, 226), and (261) inner membrane potential is decreased (117, 189, 190, 265), or when ROS production is elevated (233, 234) (Fig.”
Impairment of autophagy: From hereditary disorder to drug intoxication
Aki, T., Funakoshi, T., Unuma, K., & Uemura, K. (2013) · Toxicology · doi:10.1016/j.tox.2013.07.001 · Cited by 46
Hsp90 regulation of mitochondrial protein folding: from organelle integrity to cellular homeostasis
Altieri, D. C. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1177-0 · Cited by 46
“There is extensive evidence linking autophagy to the control of mitochondrial function [52], and data have also suggested that changes in the organelle protein folding environment couples to autophagy as a way to clear damaged and potentially noxious mitochondria [53].”
Rzezniczak, T. Z., & Merritt, T. J. S. (2012) · G3 Genes Genomes Genetics · doi:10.1534/g3.112.003715 · Cited by 46
“Interestingly, several studies have found that starvation can induce a certain level of oxidative stress (Scherz-Shouval et al. 2007; Chen et al. 2009), likely due to an upregulation of peroxisomal b-oxidation (Van den Branden et al. 1984).”
BackgroundThe cytotoxic and genotoxic effects of metalaxy-M on earthworms ( Eisenia fetida )
Liu, T., Zhu, L., Han, Y., Wang, J., Wang, J., & Zhao, Y. (2014) · Environmental Toxicology and Chemistry · doi:10.1002/etc.2682 · Cited by 46
“Previous studies have shown that ROS may contribute to the survival or death of cells, and many disease states are associated with elevated levels of ROS and increased oxidative stress [23,42,43].”
BackgroundEmerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma
Niture, S. K., Lin, M., Ríos-Colón, L., Qi, Q., Moore, J. T., & Kumar, D. (2021) · International Journal of Hepatology · doi:10.1155/2021/6675762 · Cited by 44
“Acute ethanol treatment triggered autophagy through the production of ROS, mediated by ADH and CYP2E1 enzymes, and by inactivation of the ATG4B protein [80].”
BackgroundUp‐regulation of autophagy in small intestine Paneth cells in response to total‐body γ‐irradiation
Gorbunov, N. V., & Kiang, J. G. (2009) · The Journal of Pathology · doi:10.1002/path.2591 · Cited by 48
“One of the explanations for the mAG effect in the presented model is iNOS/NOdependent post-transcriptional expression of LC3-I, followed by redox-dependent conversion of LC3-I to LC3-II mediated by Atg4 [9,22,38,39].”
BackgroundMitochondrial respiration supports autophagy to provide stress resistance during quiescence
Novais, S. M., Blecha, J., Naraine, R., Mikesova, J., Abaffy, P., Pecinová, A., Milošević, M., Bohuslavová, R., Procházka, J., Khan, S., et al. (2022) · Autophagy · doi:10.1080/15548627.2022.2038898 · Cited by 46
“How does OXPHOS, the main producer of intracellular ROS, induce protection against oxidative stress in quiescent cells? We propose that this is an active process where continuous low-level generation of endogenous ROS from the ETC attenuates the activity of ATG4B, a redox-regulated member of the autophagy cascade [38].”
BackgroundInfluentialNavigating the redox landscape: reactive oxygen species in regulation of cell cycle
Mackova, V., Raudenská, M., Polanska, H. H., Jakubek, M., & Masařík, M. (2024) · Redox Report · doi:10.1080/13510002.2024.2371173 · Cited by 48
“The oxidation inhibits the function of Atg4 and facilitates the required lipidation of Atg8, contributing to the autophagic process [91].”
Cabrera-Serrano, A. J., Sánchez‐Maldonado, J. M., González‐Olmedo, C., Carretero-Fernández, M., Díaz-Beltrán, L., Gutiérrez‐Bautista, J. F., García‐Verdejo, F. J., Gálvez-Montosa, F., López-López, J. A., García-Martín, P., et al. (2025) · Antioxidants · doi:10.3390/antiox14030264 · Cited by 50
Lim, S. W., Hyoung, B. J., Piao, S. G., Doh, K. C., Chung, B. H., & Yang, C. W. (2012) · Transplantation · doi:10.1097/tp.0b013e31825ace5c · Cited by 45
Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells
Oh, J., Choi, E., Carp, R. I., & Kim, Y. (2012) · Autophagy · doi:10.4161/auto.21164 · Cited by 48
“However, high levels of ROS can promote cellular damage and cell death through the oxidation of lipids, proteins and DNA.38,39 To investigate further a mechanism for the protective role of PrPC in oxidative stress, we examined the alteration and differentiation of autophagy under H 2 O 2 -induced oxidative stress in h…”
BackgroundAutophagy Regulation and Integration with Cell Signaling
Hamacher‐Brady, A. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4410 · Cited by 46
“Conversely, autophagy reduces ROS through activation of the Nrf2 antioxidant response (29).”
InfluentialBouhidel, J. O., Wang, P., Siu, K. L., Li, H., Youn, J. Y., & Cai, H. “. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.06.005 · Cited by 44
“However, cardiac autophagy is increased in response to oxidative stress, ATP depletion and mPTP opening [43,44].”
BackgroundNair, R. R., Emmons, M. F., Cress, A. E., Argilagos, R. F., Lam, K. S., Kerr, W. T., Wang, H., Dalton, W. S., & Hazlehurst, L. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0113 · Cited by 47
“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.”
ResultKurahashi, T., Hamashima, S., Shirato, T., Lee, J., Homma, T., Kang, E. S., & Fujii, J. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.10.052 · Cited by 45
Reactive oxygen species generated from skeletal muscles are required for gecko tail regeneration
Zhang, Q., Wang, Y., Man, L., Zhu, Z., Bai, X., Wei, S., Liu, M., Liu, M., Wang, X., Gu, X., et al. (2016) · Scientific Reports · doi:10.1038/srep20752 · Cited by 45
Solhjou, Z., Uehara, M., Bahmani, B., Maarouf, O. H., Ichimura, T., Brooks, C. R., Xu, W., Yilmaz, M., Elkhal, A., Tullius, S. G., et al. (2017) · American Journal of Transplantation · doi:10.1111/ajt.14266 · Cited by 46
“Mitochondrial damage in OS-DCs has been reported to increase autophagy (44,45).”
BackgroundMonitoring Autophagy in the Model Green Microalga Chlamydomonas reinhardtii
Pérez‐Pérez, M. E., Couso, I., Heredia-Martínez, L. G., & Crespo, J. L. (2017) · Cells · doi:10.3390/cells6040036 · Cited by 45
“In humans, the activity of ATG4A/B is inhibited by oxidation in a process that involves a cysteine residue close to the catalytic cysteine [30].”
BackgroundLiu, Y., Li, D., He, Z., Liu, Q., Wu, J., Guan, X., Tao, Z., & Deng, Y. (2017) · Oncotarget · doi:10.18632/oncotarget.23383 · Cited by 45
Lipopolysaccharide (LPS)-Induced Autophagy Is Responsible for Enhanced Osteoclastogenesis.
Sul, O., Park, H.-J., Son, H.-J., & Choi, H. (2017) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2017.0230 · Cited by 45
“Administration of NAC reduced the induction of autophagy by lowering ROS in neurons (Scherz-Shouval et al., 2007), whereas stimulation of NOX promoted autophagy in phagosomes (Kirkland et al., 2002).”
BackgroundThe true colors of autophagy in doxorubicin‑induced cardiotoxicity (Review)
Xiao, B., Hong, L., Cai, X., Mei, S., Ping, Z., & Shao, L. (2019) · Oncology Letters · doi:10.3892/ol.2019.10576 · Cited by 47
“However, in DOX-induced cardiotoxicity conditions, ATG4 protease activity is inhibited by the oxidization of cysteine residues (39).”
BackgroundDifferentiation of Cancer Stem Cells through Nanoparticle Surface Engineering
Geng, Y., Amante, J. J., Goel, H. L., Zhang, X., Walker, M. R., Luther, D. C., Mercurio, A. M., & Rotello, V. M. (2020) · ACS Nano · doi:10.1021/acsnano.0c05589 · Cited by 46
Mehta, S. L., Lin, Y., Chen, W., Yu, F., Cao, L., He, Q., Chan, P. H., & Li, P. A. (2011) · Translational Stroke Research · doi:10.1007/s12975-010-0027-3 · Cited by 36
“Autophagy plays an important role in response to oxidative stress, and it also determines the mass and integrity of mitochondria [8].”
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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