The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
Mariño, G., Urı́a, J. A., Puente, X. S., Quesada, V., Bordallo, J., & López-Otı́n, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208247200 · Cited by 206
RetractedRepertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351
LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., & Yoshimori, T. (2000) · The EMBO Journal · doi:10.1093/emboj/19.21.5720 · Cited by 6,605
Cui, C., Cui, J., Jin, F., Cui, Y., Li, R., Jiang, X., Tian, Y., Wang, R. C., Jiang, P., & Gao, J. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000479571 · Cited by 5,214
Antimicrobial Autophagy: A Conserved Innate Immune Response in Drosophila
Moy, R. H., & Cherry, S. R. (2013) · Journal of Innate Immunity · doi:10.1159/000350326 · Cited by 3,551
Autophagy in Health and Disease: A Double-Edged Sword
Shintani, T., & Klionsky, D. J. (2004) · Science · doi:10.1126/science.1099993 · Cited by 2,559
A ubiquitin-like system mediates protein lipidation
Ichimura, Y., Kirisako, T., Takao, T., Satomi, Y., Shimonishi, Y., Ishihara, N., Mizushima, N., Tanida, I., Kominami, E., Ohsumi, M., et al. (2000) · Nature · doi:10.1038/35044114 · Cited by 2,139
LC3 conjugation system in mammalian autophagy
Tanida, I., Ueno, T., & Kominami, E. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.05.009 · Cited by 1,512
WWW-query: An on-line retrieval system for biological sequence banks
Perrière, G., & Gouy, M. (1996) · Biochimie · doi:10.1016/0300-9084(96)84768-7 · Cited by 1,488
LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation
Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., & Yoshimori, T. (2004) · Journal of Cell Science · doi:10.1242/jcs.01131 · Cited by 1,394
Cited by
Sorted by citations
Items 401–500 of 1,003
Fukui, M., Kang, K. S., Okada, K., & Zhu, B. T. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24354 · Cited by 134
“ROLE OF AUTOPHAGY INDUCTION BY EPA IN MODULATING THE DEATH OF CULTURED HUMAN PANCREATIC CANCER CELLS While ROS accumulation in cancer cells often induces apoptosis, recent studies have shown that ROS can also induce autophagy under certain conditions [Yu et al., 2006; Scherz-Shouval et al., 2007].”
BackgroundLiang, D., Meyer, L. A., Chang, D. W., Lin, J. M., Pu, X., Ye, Y., Gu, J. H., Wu, X., & Lu, K. H. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0130 · Cited by 131
“ATG4A encodes a cysteine protease involved in autophagy (17).”
Autophagy proteins in macroendocytic engulfment
Florey, O., & Overholtzer, M. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.04.005 · Cited by 139
“Atg4 can also be inhibited by ROS, possibly through oxidation of a critical cysteine proximal to its catalytic site [68].”
Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation
Lee, S., Ryter, S. W., Xu, J., Nakahira, K., Kim, H. P., Choi, A. M. K., & Kim, Y. S. (2011) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0352oc · Cited by 131
“For example, starvation, a well known activator of autophagy, was associated with increased intracellular ROS production in CHO and HeLa cells (36).”
BackgroundZhang, N., Chen, Y., Jiang, R., Li, E., Chen, X., Xi, Z., Guo, Y., Liu, X., Zhou, Y., Che, Y., et al. (2011) · Autophagy · doi:10.4161/auto.7.6.15103 · Cited by 134
Regulation of the autophagic machinery in human neutrophils
Mitroulis, I., Kourtzelis, I., Kambas, K., Rafail, S., Chrysanthopoulou, A., Speletas, M., & Ritis, K. (2010) · European Journal of Immunology · doi:10.1002/eji.200940025 · Cited by 132
Yan, W., Zhang, H., Bai, X., Lü, Y., Dong, H., & Xiong, L. (2011) · Brain Research · doi:10.1016/j.brainres.2011.05.049 · Cited by 129
“Accumulating evidence demonstrate that exogenous or endogenous ROS, served as important signaling molecules, participates in the activation of autophagy, which can protect cells from damage in stressful and pathological conditions (Djavaheri-Mergny et al., 2006; Scherz-Shouval et al., 2007).”
Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease
Kaushal, G. P., Chandrashekar, K., & Juncos, L. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20153791 · Cited by 130
“(Top right) H2O2 oxidizes the cysteine 81 residue of Atg4, which inactivates the protease to facilitate Atg8 in the formation of autophagosome.”
BackgroundPexophagy: A Model for Selective Autophagy
Germain, K., & Kim, P. K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020578 · Cited by 133
“Furthermore, autophagy can be induced by environmental stimuli such as ROS, hypoxia or starvation, to generate metabolites that can be used for de novo biomolecule synthesis or as substrates for energy production [50,54,55].”
BackgroundSystems biology of the autophagy-lysosomal pathway
Jegga, A. G., Schneider, L. E., Ouyang, X., & Zhang, J. (2011) · Autophagy · doi:10.4161/auto.7.5.14811 · Cited by 129
“38 Accumulation of reactive oxygen species can in turn regulate autophagy by modifying ATG4.”
BackgroundSubstrate specificity of the ubiquitin and Ubl proteases
Ronau, J. A., Beckmann, J. F., & Hochstrasser, M. (2016) · Cell Research · doi:10.1038/cr.2016.38 · Cited by 129
Mitophagy: Link to cancer development and therapy
Kulikov, A. V., Luchkina, E. A., Gogvadze, V. G., & Zhivotovsky, B. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.10.088 · Cited by 132
Defective Autophagy in Parkinson’s Disease: Role of Oxidative Stress
Janda, E., Isidoro, C., Carresi, C., & Mollace, V. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8318-1 · Cited by 134
“Accordingly, H 2 O 2 blocks the delipidation activity of Atg4 (following oxidation of Cys81) and stabilizes LC3II, while the potent antioxidant DTT strongly reverses this effect activating the delipidation of GATA-16 and LC3II [132].”
BackgroundInfluentialCeramide induced mitophagy and tumor suppression
Dany, M., & Öğretmen, B. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.12.039 · Cited by 130
Astrocyte Depletion Impairs Redox Homeostasis and Triggers Neuronal Loss in the Adult CNS
Schreiner, B., Romanelli, E., Liberski, P. P., Ingold‐Heppner, B., Sobottka, B., Hartwig, T., Chandrasekar, V., Johannssen, H. C., Zeilhofer, H. U., Aguzzi, A., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.051 · Cited by 129
“A disturbed redox balance in our model would also be consistent with the ultrastructural signs of abnormal autophagic activity that we observed in degenerating neurons (Figures 3F–3H; Scherz-Shouval et al., 2007).”
ResultBharath, L. P., Mueller, R., Li, Y., Ruan, T., Kunz, D., Goodrich, R., Mills, T. J., Deeter, L., Sargsyan, A., Babu, P. V. A., et al. (2014) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2014-0017 · Cited by 131
“Fasting increases ROS in a PI3K-dependent manner, and antioxidant treatment negates fasting-induced autophagy (Scherz-Shouval et al. 2007).”
BackgroundConsensus Paper: Pathological Mechanisms Underlying Neurodegeneration in Spinocerebellar Ataxias
Matilla‐Dueñas, A., Ashizawa, T., Brice, A., Magri, S., McFarland, K. N., Pandolfo, M., Pulst, S. M., Rieß, O., Rubinsztein, D. C., Schmidt, J., et al. (2013) · The Cerebellum · doi:10.1007/s12311-013-0539-y · Cited by 132
“It can be stimulated by a wide range of physiological stimuli (like oxidative stress) or drugs (like rapamycin) [154, 155].”
BackgroundHatem, E., Banna, N. E., & Huang, M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7134 · Cited by 127
Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect
Lim, S. M., Hanif, E. A. M., & Chin, S. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00570-z · Cited by 138
“Upon starvation, the production of ROS triggers autophagy, specifically, H2O2 reversibly modifies the cysteine residues of ATG4 and thereby disrupts the active site required for delipidation of LC3 [79, 80].”
BackgroundAssessment of the Lung Toxicity of Copper Oxide Nanoparticles: Current Status
Ahamed, M., Akhtar, M. J., Alhadlaq, H. A., & Alrokayan, S. (2015) · Nanomedicine · doi:10.2217/nnm.15.72 · Cited by 130
Vertical inhibition of the PI3K/Akt/mTOR pathway for the treatment of osteoarthritis
Chen, J., Crawford, R., & Xiao, Y. (2012) · Journal of Cellular Biochemistry · doi:10.1002/jcb.24362 · Cited by 127
“Inhibition of NF-kB can lead to increased ROS, which enhances autophagy [Scherz-Shouval et al., 2007].”
BackgroundRedox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response
Zhang, L., Wang, K., Lei, Y., Li, Q., Nice, E. C., & Huang, C. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.08.030 · Cited by 127
“Both exogenous and starvation-induced H2O2 inhibit the cleavage activity of ATG4 by oxidizing a cysteine residue (Cys 81) located near the catalytic site, as mutation at Cys81 (Cys81Ser) reduces the redox sensitivity of ATG4 and prevents the formation of autophagosomes in cells [92].”
HIV-1 Induced Bystander Apoptosis
Garg, H., Mohl, J. E., & Joshi, A. (2012) · Viruses · doi:10.3390/v4113020 · Cited by 136
“Proteomic analysis and use of inhibitors suggest an accumulation of Reactive Oxygen Species (ROS) in autophagic bystander cells [98].”
BackgroundD’Anneo, A., Carlisi, D., Lauricella, M., Puleio, R., Martinez, R., Bella, S. D., Marco, P. D., Emanuele, S., Fiore, R. D., Guercio, A., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.415 · Cited by 126
“It seems that ROS are essential for autophagy as they regulate Atg4, a cysteine protease involved in the process.(47) Moreover, JNK and RIP-1 exerted a stimulatory role in this process, as their specific inhibitors SP600125 and Nec-1 prevented both positivity to MDC test and enhancement in LC3-II level.”
BackgroundHasanain, M., Bhattacharjee, A., Pandey, P., Ashraf, R., Singh, N., Sharma, S., Vishwakarma, A. L., Datta, D. B., Mitra, K., & Sarkar, J. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.219 · Cited by 126
“may have inactivated Atg4 and consequently promoted LC3B lipidation to induce autophagy.(38) Collectively, our data indicate”
BackgroundShiroto, T., Romero, N., Sugiyama, T., Sartoretto, J. L., Kalwa, H., Yan, Z., Shimokawa, H., & Michel, T. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087871 · Cited by 125
“Oxidative stress may play a role in autophagy, although the molecular mechanisms remain incompletely understood [33,43,44,45].”
BackgroundCholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion
Barbero-Camps, E., Roca-Agujetas, V., Bartolessis, I., de Dios, C., Fernández-Checa, J. C., Marí, M., Morales, A., Hartmann, T., & Colell, A. (2018) · Autophagy · doi:10.1080/15548627.2018.1438807 · Cited by 125
“describe a local rise in H2O2, upon starvation-induced autophagy, which transiently oxidizes and inactivates ATG4B allowing the conjugation of lipidated Atg8-family proteins to the phagophore membranes [47].”
BackgroundZinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line
Hwang, J. J., Kim, H., Kim, J., Cho, D.-H., Kim, M. J., Kim, Y.-S., Kim, Y., Park, S. J., & Koh, J. (2010) · BioMetals · doi:10.1007/s10534-010-9346-9 · Cited by 124
“Other mechanisms activated in autophagic cell death include reactive oxygen species (ROS) generation by NADPH oxidase (Chen et al. 2008; Scherz-Shouval et al. 2007), downregulation of the antiapoptotic proteins Bcl-XL and Bcl-2 (Feng et al.”
Role of plant autophagy in stress response
Han, S., Yu, B., Wang, Y., & Liu, Y. (2011) · Protein & Cell · doi:10.1007/s13238-011-1104-4 · Cited by 124
“In mammal cells, nutrient starvation leads to ROS accumulation, specifically H2O2 in the mitochondria, thereby inducing autophagy (Scherz-Shouval et al., 2007).”
BackgroundAutophagy and innate immunity: Triggering, targeting and tuning
Sumpter, R., & Levine, B. (2010) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2010.04.003 · Cited by 129
Dai, J.-P., Zhao, X.-F., Zeng, J., Wan, Q.-Y., Yang, J.-C., Li, W.-Z., Chen, X.-X., Wang, G.-F., & Li, K.-S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061026 · Cited by 123
“H2O2 can promote autophagy by inhibiting Atg4 [20].”
BackgroundThe emerging role of autophagy in alcoholic liver disease
Ding, W., Manley, S., & Ni, H. (2011) · Experimental Biology and Medicine · doi:10.1258/ebm.2011.010360 · Cited by 122
Zhang, T., Li, Y., Park, K. A., Byun, H. S., Won, M., Jeon, J., Lee, Y., Seok, J. H., Choi, S. W., Lee, S. S., et al. (2012) · Autophagy · doi:10.4161/auto.18867 · Cited by 125
“Recently, several reports provided evidence for the involvement of reactive oxygen species (ROS) in the induction of autophagy in response to chemotherapy-induced stress.(38,39) Furthermore, previous study(28) has shown that cucurbitacin-B could induce the accumulation of ROS through a STAT3-independent mechanism.”
BackgroundULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy
Li, T. Y., Sun, Y., Liang, Y., Liu, Q., Shi, Y., Zhang, C., Zhang, C., Song, L., Zhang, P., Zhang, X., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.04.009 · Cited by 124
“Importantly, the increasedHKenzymatic activityanddecreased activities of PFK1 and ENO1 during ULK1/2 activation may increase the ratio of glucose flux going through PPP to keep generating reducing forces to eliminate the elevated ROS during amino acid and serum deprivation (Scherz-Shouval et al., 2007).”
BackgroundRole of Parkin and endurance training on mitochondrial turnover in skeletal muscle
Chen, C. C. W., Erlich, A. T., & Hood, D. A. (2018) · Skeletal Muscle · doi:10.1186/s13395-018-0157-y · Cited by 124
“Lipidated microtubule-associated protein-light chain 3 (LC3II) is a protein bound on the phagophore membrane that can associate with p62 [44, 45], ultimately resulting in the autophagosomal enclosure of dysfunctional mitochondria as a cellular safeguard from additional oxidative damage [46].”
BackgroundRyter, S. W., & Choi, A. M. K. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200909-101js · Cited by 122
“The autophagic inhibitor, 3MA, or knockdown of specific autophagy genes (i.e., beclin 1, Atg5, Atg7) with siRNA, prevented H2O2-induced autophagic cell death (67).”
InfluentialDevi, T. S., Somayajulu, M., Kowluru, R. A., & Singh, L. P. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.190 · Cited by 122
“The delipidating activity of ATG4B is known to be inhibited by cysteine oxidation (Cys81) near its protease active site (Cys77) during oxidative stress.(19,20) To further proceed to the mitophagic flux, adapter proteins, such as optineurin (OPTN) and p62/sequestrome 1 (SQSTM1), which are receptors for ubiquitin-tagged…”
BackgroundOxidative Stress and Cancer Therapy: Controlling Cancer Cells Using Reactive Oxygen Species
Ju, S., Singh, M. K., Han, S., Ranbhise, J. S., Ha, J., Choe, W., Yoon, K., Yeo, S. G., Kim, S. S., & Kang, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212387 · Cited by 135
“This inactivation prevents LC3 from dissociating from PE on the autophagosome membrane, thereby promoting autophagy [166].”
Glutathione Participates in the Regulation of Mitophagy in Yeast
Deffieu, M. S., Bhatia‐Kiššová, I., Salin, B., Galinier, A., Manon, S., & Camougrand, N. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.005181 · Cited by 124
Autophagy in regulation of Toll-like receptor signaling
Into, T., Inomata, M., Takayama, E., & Takigawa, T. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2012.01.020 · Cited by 121
7-Ketocholesterol Induces Autophagy in Vascular Smooth Muscle Cells through Nox4 and Atg4B
He, C., Zhu, H., Zhang, W., Okon, I. S., Wang, Q., Li, H., Le, Y.-Z., & Xie, Z. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.04.028 · Cited by 123
“They concluded that the delipidation activity of Atg4 is the main target of this regulation.(8) In our system, 7-KC enhanced intracelluar hydrogen peroxide, reduced Atg4B activity, and increased autophagic capacity.”
InfluentialLv, H., Yang, H., Wang, Z., Feng, H., Deng, X., Cheng, G., & Ci, X. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1543-z · Cited by 124
Autophagy and Parkinson’s Disease
Lu, J., Wu, M., & Yue, Z. (2020) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-15-4272-5_2 · Cited by 131
Multi-site control and regulation of mitochondrial energy production
Bénard, G., Bellancé, N., José, C., Melser, S., Nouette‐Gaulain, K., & Rossignol, R. (2010) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2010.02.030 · Cited by 126
“ROS that alter mitochondria are also implicated in this mechanism [135].”
BackgroundSingh, N., Lawana, V., Luo, J. D., Phong, P., Abdalla, A., Palanisamy, B. N., Rokad, D., Sarkar, S., Jin, H., Anantharam, V., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.019 · Cited by 120
Cadmium Toxicity toward Autophagy through ROS-Activated GSK-3β in Mesangial Cells
Wang, S.-H., Shih, Y., Kuo, T.-C., Ko, W., & Shih, C.-M. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfn266 · Cited by 120
“In addition, NAC and catalase can decrease the ratio of autophagy, suggesting that ROS are necessary for the induction of Downloaded from https://academic.oup.com/toxsci/article-abstract/108/1/124/1673832 by guest on 27 July 2018 autophagy (Scherz-Shouval et al., 2007).”
BackgroundResultInfluentialMitochondrial ROS and mitochondria-targeted antioxidants in the aged heart
Bou‐Teen, D., Kaludercic, N., Weissman, D., Turan, B., Maack, C., Lisa, F. D., & Ruiz‐Meana, M. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.043 · Cited by 119
Mitochondrial quality control: Easy come, easy go
Stotland, A. B., & Gottlieb, R. A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.12.041 · Cited by 123
Ion channels in the regulation of autophagy
Kondratskyi, A., Kondratska, K., Skryma, R. N., Klionsky, D. J., & Prevarskaya, N. B. (2017) · Autophagy · doi:10.1080/15548627.2017.1384887 · Cited by 121
“Of note, the ATG4 family of cysteine proteases serve to cleave LC3-I near the C terminus, thus allowing its subsequent conjugation to phosphatidylethanolamine (PE) and incorporation into the phagophore membrane.(146) Considering that LC3 plays an essential role in phagophore membrane expansion, and closure as well as…”
BackgroundXiao, B., Deng, X., Lim, G. G. Y., Xie, S., Zhou, Z. D., Lim, K.-L., & Tan, E.-K. (2017) · Cell Death & Disease · doi:10.1038/cddis.2017.463 · Cited by 117
“to modify a cysteine residue near the catalytic domain of ATG4, thereby activating autophagy.(7) In addition, Chen et al.”
Sanabria, L. M., Rodríguez, M. E., Cogno, I. S., Vittar, N. B. R., Pansa, M. F., Lamberti, M. J., & Rivarola, V. A. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.10.001 · Cited by 120
de Prati, A. C., Butturini, E., Rigo, A., Oppici, E., Rossin, M., Boriero, D., & Mariotto, S. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25972 · Cited by 121
“On the other hand, lot of literatures describe that oxidative stress induced by the ROS increase and GSH depletion maybe directly correlated with autophagy activation [Scherz-Shouval et al., 2007; Gao et al., 2008; Li et al., 2012; Poillet-Perez et al., 2015].”
BackgroundArnold, S. (2011) · Mitochondrion · doi:10.1016/j.mito.2011.05.003 · Cited by 117
The multifaceted role of mitochondria in autism spectrum disorder
Khaliulin, I., Hamoudi, W., & Amal, H. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02725-z · Cited by 128
“Upon cellular stress, characteristic of ASD [158], ROS production and elevated intracellular Ca 2 + concentration trigger mPTP opening leading to mitochondrial membrane permeabilization (MMP) [181], initiating apoptosis and necrosis [269], and regulating the activity of autophagy [270, 271].”
Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells
Desideri, E., Filomeni, G., & Ciriolo, M. R. (2012) · Autophagy · doi:10.4161/auto.22037 · Cited by 119
“Scherz-Shouval et al.(11) have demonstrated that ROS are essential for starvation-induced autophagy and specifically target ATG4, a thiol-containing protein involved in the initial step of autophagosome formation, thus affecting its proteolytic function.”
BackgroundInfluentialRyter, S. W., Bhatia, D., & Choi, M. E. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7518 · Cited by 117
Yi, J., Wu, S., Tan, S., Qin, Y., Wang, X., Jiang, J., Liu, H., & Wu, B. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00768-7 · Cited by 117
“Autophagy is one of the most important mechanisms in regulating ROS [12].”
BackgroundDong, Y., Undyala, V. V. R., Gottlieb, R. A., Mentzer, R. M., & Przyklenk, K. (2010) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248410370327 · Cited by 115
“For example, ROS production has direct effects on Atg4, leading to upregulation of autophagy—a process that may be independent of Beclin 1 signaling.(55,56) With regard to calcium, chelation of Ca2þ with BAPTA-AM or depletion of sarco/ endoplasmic reticular (S/ER) calcium stores with thapsigargin was shown to suppress…”
BackgroundThis old heart: Cardiac aging and autophagy
Linton, P., Gurney, M. A., Sengstock, D. M., Mentzer, R. M., & Gottlieb, R. A. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.12.017 · Cited by 115
“Third, ROS have been shown to induce autophagy in vitro via AMPK activation [64] and/or by regulating Atg4 activity in vitro [65], establishing that the cellular response to ROS involves autophagy, likely as a mechanism to limit further ROS production from damaged mitochondria and potentially as a means to eliminate o…”
BackgroundYen, Y.-T., Yang, H.-R., Lo, H., Hsieh, Y., Tsai, S., Hong, C.-W., & Hsieh, C. (2013) · Surgery · doi:10.1016/j.surg.2012.11.021 · Cited by 114
Ding, W., Ni, H., Gao, W., Chen, X., Kang, J. H., Stolz, D. B., Liu, J., & Yin, X. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-1169 · Cited by 117
“ROS may also have a more direct effect on autophagy induction via the regulation of Atg4B, which is required for LC3 processing during starvation (34).”
BackgroundKuang, E., Okumura, C. Y. M., Sheffy-Levin, S., Varsano, T., Shu, V. C.-W., Qi, J., Niesman, I. R., Yang, H., López-Otı́n, C., Yang, W. Y., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003007 · Cited by 115
“Initial data supports the role of ROS in the association between RNF5 and ATG4B (both proteins contain cysteine-rich domains that are required for their function), which is consistent with a reported role for ROS in autophagy [42].”
BackgroundAutophagy and Rheumatoid Arthritis: Current Knowledges and Future Perspectives
Vomero, M., Barbati, C., Colasanti, T., Perricone, C., Novelli, L., Ceccarelli, F., Spinelli, F. R., Franco, M. D., Conti, F., Valesini, G., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01577 · Cited by 116
“Since it has been demonstrated an involvement of ROS in autophagosome formation by regulation of Atg4 function (85), ROS-mediated autophagy induction could contribute to the resistance of apoptosis found in synovial and peripheral RA T cells and to the generation of citrullinated peptides in APCs, both these aspects w…”
BackgroundLaureano‐Marín, A. M., Aroca, Á., Pérez‐Pérez, M. E., Yruela, I., Jurado-Flores, A., Moreno, I., Crespo, J. L., Romero, L. C., & Gotor, C. (2020) · The Plant Cell · doi:10.1105/tpc.20.00766 · Cited by 115
Fighting disease by selective autophagy of aggregate‐prone proteins
Knævelsrud, H., & Simonsen, A. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.04.041 · Cited by 119
“late by age, has been found to inactivate Atg4, thus inhibiting LC3 delipidation and potentially promoting autophagy [76].”
BackgroundDang, S., Xu, H., Xu, C., Cai, W., Li, Q., Cheng, Y., Jin, M., Wang, R., Peng, Y., Zhang, Y., et al. (2014) · Autophagy · doi:10.4161/auto.28771 · Cited by 115
“Cell surface marker analysis confirmed that MSCs were positive for CD44 (12-0441-81) and LY6A (175981-81), negative for ITGAM (12-0112-81), PECAM1 (120311), CD34 (11-0341-81), PTPRC (17-0451-82), MHC class I (12-5999) and MHC class II (12-5321).”
Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease
Nakahira, K., Cloonan, S. M., Mizumura, K., Choi, A. M. K., & Ryter, S. W. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5373 · Cited by 115
“In particular, autophagy represents an inducible response to oxidative stress (5, 89, 144, 145, 154).”
BackgroundInfluentialDu, Y., Meng, Q., Zhang, Q., & Guo, F. (2011) · Amino Acids · doi:10.1007/s00726-011-1123-8 · Cited by 113
“To investigate whether autophagy is involved in isoleucine or valine-induced fat loss, we examined the mRNA levels of genes encoding autophagy-related proteins including ATG4a, ATG5, ATG7, ATG8/LC3 (Scherz-Shouval et al. 2007; Noda et al. 2010; Komatsu et al. 2005; Yousefi et al. 2006).”
BackgroundMending a broken heart: the role of mitophagy in cardioprotection
Moyzis, A. G., Sadoshima, J., & Gustafsson, Å. B. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00708.2014 · Cited by 114
Choi, H., Merceron, C., Mangiavini, L., Seifert, E. L., Schipani, E., Shapiro, I. M., & Risbud, M. V. (2016) · Autophagy · doi:10.1080/15548627.2016.1192753 · Cited by 111
“thus arguing against the generation of ROS as a cause of autophagy induction.(51,52) Previous studies have shown that HIF1A contributes to autophagy regulation in hypoxia.”
BackgroundAutophagy proteins in antigen processing for presentation on MHC molecules
Münz, C. (2016) · Immunological Reviews · doi:10.1111/imr.12422 · Cited by 121
“Atg8 is cleaved from the completed outer autophagosomal membrane by Atg4 and thereby also liberates the Atg5-12/ 16L1 complex for recycling.”
BackgroundMethodInfluentialAgujetas, V. R., Barbero‐Camps, E., de Dios, C., Podlesniy, P., Abadin, X., Morales, A., Marı́, M., Trullás, R., & Colell, A. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00435-6 · Cited by 113
“These data complement previous studies that illustrate how modulation of the mitochondrial antioxidant protein superoxide dismutase-2 has a direct impact on mitophagy progression, and point to mitochondrial ROS production as an upstream inducer of the process [63, 68, 69].”
InfluentialMarañón, A., Díaz-Pozo, P., Canet, F., Díaz‐Morales, N., Abad‐Jiménez, Z., López‐Domènech, S., Vezza, T., Apostolova, N., Morillas, C., Rocha, M., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102342 · Cited by 117
“The accumulation of ROS impairs mitochondrial functionality due to the generation of mtDNA mutations and the accumulation of dysfunctional and “mitophagy-resistant” mitochondria [26,27].”
BackgroundMitochondrial Topoisomerase I is Critical for Mitochondrial Integrity and Cellular Energy Metabolism
Douarre, C., Sourbier, C., Rosa, I. D., Das, B. B., Redon, C. E., Zhang, H., Neckers, L., & Pommier, Y. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041094 · Cited by 114
“Because ROS activate autophagy [45,46] and Top1mt2/2 cells have elevated ROS production (see above), we tested autophagy induction in Top1mt2/2 cells using the autophagy marker Light Chain 3 (LC3).”
Huang, Q. B., Wu, Y., Tan, H.-L., Ong, C.-N., & Shen, H.-M. (2008) · Cell Death and Differentiation · doi:10.1038/cdd.2008.151 · Cited by 116
“An earlier study provided evidence that ROS contributes to starvation-induced autophagy through direct oxidation of autophagy-related gene (ATG) 4.(15) It remains to be determined whether and how ROS affect the autophagy regulatory mechanism upstream of ATGs.”
BackgroundResultRetractedGold Nanoparticle-Induced Cell Death and Potential Applications in Nanomedicine
Sun, H., Jia, J., Jiang, C., & Zhai, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030754 · Cited by 111
“On the other hand, the rise in ROS directly oxidized and inactivated Atg4, leading to Atg8 lipidation and autophagy induction [115].”
BackgroundKumar, A., Davuluri, G., Welch, N., Kim, A., Gangadhariah, M. H., Allawy, A., Priyadarshini, A., McMullen, M. R., Sandlers, Y. I., Willard, B. B., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.09.031 · Cited by 112
ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage
Kessel, D. H., Price, M., & Reiners, J. J. (2012) · Autophagy · doi:10.4161/auto.20792 · Cited by 111
Impaired quality control of mitochondria: Aging from a new perspective
Weber, T. A., & Reichert, A. S. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.03.018 · Cited by 112
“Despite their destructive potential ROS are essential for cellular functions since they also act as signaling molecules (Veal et al., 2007) and by that are involved in a number of pro-survival pathways (Brigelius- Flohe, 2009); e.g. ROS are important in autophagy (Scherz-Shouval et al., 2007).”
BackgroundRegulation of macroautophagy in Saccharomyces cerevisiae
Inoue, Y., & Klionsky, D. J. (2010) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2010.03.009 · Cited by 113
The yeast autophagy protease Atg4 is regulated by thioredoxin
Pérez‐Pérez, M. E., Zaffagnini, M., Marchand, C. H., Crespo, J. L., & Lemaire, S. D. (2014) · Autophagy · doi:10.4161/auto.34396 · Cited by 117
“At present, Atg4 is the only Atg protein whose activity has been shown to be redox regulated.(18,22) In human ATG4A and ATG4B, this regulation was proposed to involve Cys81, possibly by interfering with the activity of the nearby catalytic Cys77.”
BackgroundInfluentialNutrient-sensing mTORC1: Integration of metabolic and autophagic signals
Tan, V. P., & Miyamoto, S. (2016) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2016.01.005 · Cited by 113
“For example, ROS, specifically hydrogen peroxide (H2O2), directly activate autophagy during nutrient starvation by oxidization and inhibition of ATG4 and subsequent increase in LC3 lipidation [192].”
Wu, C.-A., Chao, Y., Shiah, S., & Lin, W. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.01.025 · Cited by 111
Angiotensin II and Oxidative Stress in the Failing Heart
Zablocki, D., & Sadoshima, J. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4588 · Cited by 110
“A recent study demonstrated that ROS play an essential role in starvation-induced autophagy by inhibiting the Atg4 cysteine protease through a redox-dependent mechanism (106).”
BackgroundNADPH Oxidases in Lung Health and Disease
Bernard, K. F., Hecker, L., Luckhardt, T., Cheng, G., & Thannickal, V. J. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5608 · Cited by 112
“Nonimmune mediated functions of Noxderived ROS include, but are not limited to cell growth, proliferation, angiogenesis, apoptosis, and autophagy (22, 48, 52, 89, 133).”
BackgroundThe Interrelation between Reactive Oxygen Species and Autophagy in Neurological Disorders
Fang, C., Gu, L., Smerin, D., Mao, S., & Xiong, X. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/8495160 · Cited by 114
“Neurons are highly sensitive to autophagic degradation, and the integrity of mature neurons depends on the high level of autophagy because of their postmitotic nature [14, 137].”
BackgroundMichalska, P., & Leon, R. M. (2020) · Antioxidants · doi:10.3390/antiox9080740 · Cited by 119
Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma
Guo, X., Li, D., Sun, K., Wang, J., Liu, Y., Song, J., Zhao, Q., Zhang, S., Deng, W.-J., Zhao, X., et al. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0966-0 · Cited by 111
“ROS, especially mitochondrial ROS, serve as signaling molecules in inducing autophagy [32, 33].”
BackgroundThe novel relationship between Sirt3 and autophagy in myocardial ischemia–reperfusion
Zheng, Y., Shi, B., Ma, M., Wu, X., & Lin, X. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27329 · Cited by 108
Mitochondrial Electron Transport Chain Complex III Is Required for Antimycin A to Inhibit Autophagy
Ma, X., Jin, M., Cai, Y. C., Xia, H., Long, K., Liu, J., Yu, Q., & Yuan, J. (2011) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.08.009 · Cited by 116
“1476 Chemistry & Biology 18, 1474–1481, November 23, 2011 a2011 (Lipinski et al., 2010; Scherz-Shouval and Elazar, 2007; Scherz-Shouval et al., 2007).”
BackgroundPoornima, P., Weng, C., & Padma, V. V. (2013) · Food Chemistry · doi:10.1016/j.foodchem.2013.05.138 · Cited by 108
“In addition, ROS are known to be signalling molecules in autophagy mediated cell death (Scherz-Shouval et al., 2007).”
BackgroundJung, K. H., Noh, J. H., Kim, J. K., Eun, J. W., Bae, H. J., Chang, Y. G., Kim, M., Park, W. S., Lee, J. Y., Lee, S.-Y., et al. (2012) · Hepatology · doi:10.1002/hep.25699 · Cited by 110
“Recent investigations have indicated that JNK is activated during autophagy and that this is required for autophagosome formation, although the underlying mechanism has not been determined.(20) It has also been reported that the activation of JNK-mediated Beclin 1 expression by anticancer agents induces autophagic cel…”
BackgroundImplications of autophagy for vascular smooth muscle cell function and plasticity
Salabei, J. K., & Hill, B. G. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.08.003 · Cited by 108
“Administration of 7-KC to VSMCs promoted upregulation of NADPH oxidase 4 (Nox4) and increased H2O2 production, which resulted in inhibition of Atg4B activity.”
BackgroundAutophagy and senescence in cancer therapy
Gewirtz, D. A. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24420 · Cited by 110
Endoplasmic reticulum stress induces autophagy in renal proximal tubular cells
Kawakami, T., Inagi, R., Takano, H., Sato, S., Ingelfinger, J. R., Fujita, T., & Nangaku, M. (2009) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfp215 · Cited by 109
“Here, given that autophagy can also be induced by reactive oxygen species [57,58], we also investigated whether oxidative stress mediates the induction of autophagy by ER stress using the antioxidants N-acetyl cysteine and ascorbic acid, but saw no effect for either (data not shown).”
BackgroundChen, N., Wu, L., Yuan, H., & Wang, J. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.10564 · Cited by 107
“ROS is essential for starvation induced autophagy by oxidative inactivation of Atg4 and facilitating autophagosome formation [47].”
BackgroundC10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy
Salcher, S., Hermann, M., Kiechl‐Kohlendorfer, U., Ausserlechner, M. J., & Obexer, P. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0661-4 · Cited by 107
“Under conditions of cellular stress, elevated cellular ROS levels contribute to the induction of autophagy [18, 19].”
BackgroundMontani, M. S. G., Santarelli, R., Granato, M., Gonnella, R., Torrisi, M. R., Faggioni, A., & Cirone, M. (2018) · Autophagy · doi:10.1080/15548627.2018.1536530 · Cited by 108
“One of the stimuli that upregulates autophagy is the increase of intracellular reactive oxygen species (ROS) [26,27].”
BackgroundNeuronal autophagy in cerebral ischemia – a potential target for neuroprotective strategies?
Gabryel, B., Kost, A., & Kasprowska, D. (2012) · Pharmacological Reports · doi:10.1016/s1734-1140(12)70725-9 · Cited by 106
“It was shown that H2O2 generated in oxidative conditions causes inactivation of cysteine protease Atg4 at the site of autophagosome formation, thereby promoting LC3 conversion – an essential step in the process of autophagy [81].”
BackgroundWoo, J., Park, E., & Dinesh‐Kumar, S. P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318207111 · Cited by 111
“It is proposed that nutrient starvation of human cells induces an increase in the local H2O2 concentration at the mitochondria, inactivating hAtg4s to suppress deconjugation activity, and in turn facilitating conjugation of hAtg8 to PE and autophagosome formation (17).”
BackgroundInfluential
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
