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ATF4 is an oxidative stress–inducible, prodeath transcription factor in neurons in vitro and in vivo
Open accessAbstract
Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress–inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress–induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4−/− neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4−/− mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.
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“We verified that known ATF4 target genes, Tribbles 3 (Trib3), a modulator of AKT, and Chac1, a cyclohydrolase that degrades glutathione,51”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [51]
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“GSK2606414 significantly inhibited 2-DG-induced eIF2α phosphorylation (Figures 6G and 6H) and transcription of the ATF4 target gene, Trib3, in primary neurons51”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [51]
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“ATF4 is found to be involved in a number of different physiological events, such as long-term memory (15), osteoblast differentiation (10) glucose and glycogen bisosynthesis (16), and redox homoeo-stasis (17).”
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Cruz-Rivera, Y. E., Pérez‐Morales, J., Santiago, Y. M., Gonzalez, V., Morales, L., Cabrera‐Ríos, M., & Isaza, C. E. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170799 · Cited by 22
“Deletion of ATF4 renders neurons resistant to neuronal cell death and is associated with the preservation of glutathione levels [58], as shown schematically in Fig.”
BackgroundTherapeutic Potential of Targeting the PERK Signaling Pathway in Ischemic Stroke
Yu, X., Dang, L., Zhang, R., & Yang, W. (2024) · Pharmaceuticals · doi:10.3390/ph17030353 · Cited by 22
“The relevant experimental brain ischemia studies are listed in Table 1.”
Rebalancing liver-infiltrating CCR3+ and CD206+ monocytes improves diet-induced NAFLD
Sun, G., Wang, Y., Yang, L., Zhang, Z., Zhao, Y., Shen, Z., Han, X., Du, X., Jin, H., Li, C., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112753 · Cited by 24
Sazonova, M. A., Sinyov, V. V., Ryzhkova, A. I., Sazonova, M. D., Kirichenko, T. V., Khotina, V. A., Khasanova, Z. B., Doroschuk, N. A., Karagodin, V. P., Orekhov, A. N., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020699 · Cited by 27
“on cellular and animal models detected, that ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo [179].”
BackgroundLu, C., Qin, C., Wu, J., Jiang, H., Xu, Q., Chen, J., Xu, X., Zhang, X., Guan, M., & Deng, X. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103689 · Cited by 25
“Activation of activating transcription factor 4 (ATF4) typically results in an increase in GSH levels, as ATF4 promotes GSH synthesis by upregulating the expression of γ -GCS [81].”
Melatonin: a promising neuroprotective agent for cerebral ischemia-reperfusion injury
Tozihi, M., Shademan, B., Yousefi, H., Avcı, Ç. B., Nourazarian, A., & Dehghan, G. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1227513 · Cited by 34
“This ultimately leads to the activation of cell death signals (Lange et al., 2008).”
Liu, J., Amar, F., Corona, C., So, R. W. L., Andrews, S. J., Nagy, P. L., Shelanski, M. L., & Greene, L. A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00062 · Cited by 26
“…ATF4 rapidly increase under such conditions and these in turn regulate transcription of a variety of genes that can lead either to alleviation of the stress or to cell death (Lange et al., 2008; Sun et al., 2013; Baleriola et al., 2014; Iurlaro andMuñoz-Pinedo, 2016; Pakos-Zebrucka et al., 2016).”
BackgroundDávila, D., Jimenez-Mateos, E. M., Mooney, C. M., Velasco, G., Henshall, D. C., & Prehn, J. H. M. (2014) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-08-0495 · Cited by 22
“Finally, Hsp27 overexpression did not affect other stress response genes, such as ATF4, also up-regulated during oxidative stress (Lange et al., 2008).”
BackgroundGupta, S., Biswas, J., Gupta, P., Singh, A., Tiwari, S., Mishra, A., & Singh, S. (2019) · Neurochemistry International · doi:10.1016/j.neuint.2019.104581 · Cited by 19
Nguyen, T. H., Koneru, B., Wei, S., Chen, W. H., Makena, M. R., Urias, E., Kang, M. H., & Reynolds, C. P. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0385 · Cited by 23
“ATF4 is reported as an ROS responsive gene (46), which suggests that ROS generated by 4-HPR is upstream of the Figure 2.”
BackgroundSpecificity of Stress‐Responsive Transcription Factors Nrf2, ATF4, and AP‐1
Rößler, O. G., & Thiel, G. (2016) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25619 · Cited by 22
“Likewise, AP-1/c-Jun and ATF4 have been described to respond to oxidative stress [Karin and Shaulian, 2001; Roybal et al., 2005; Ameri and Harris, 2008; Lange et al., 2008].”
BackgroundInfluentialThe Unfolded Protein Response: A Double-Edged Sword for Brain Health
Gebert, M., Sławski, J., Kalinowski, L., Collawn, J. F., & Bartoszewski, R. (2023) · Antioxidants · doi:10.3390/antiox12081648 · Cited by 21
The Proteostasis Network: A Global Therapeutic Target for Neuroprotection after Spinal Cord Injury
Whittemore, S. R., Ohri, S. S., Forston, M. D., Wei, G. Z., & Hetman, M. (2022) · Cells · doi:10.3390/cells11213339 · Cited by 18
“Current literature supports the role of ATF4 as a mediator of tissue damage in traumatic CNS injury [135,180,181].”
BackgroundFunctional validation of ATF4 and GADD34 in Neuro2a cells by CRISPR/Cas9-mediated genome editing
Oh-hashi, K., Sugiura, N., Amaya, F., Isobe, K., & Hirata, Y. (2018) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-017-3156-0 · Cited by 17
“, neurodegenerative diseases and inflammation) [3, 10, 11].”
Integrated Stress Response: Connecting ApoE4 to Memory Impairment in Alzheimer's Disease
Oliveira, M. M., & Lourenco, M. V. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4110-15.2016 · Cited by 17
“However, ATF4 overexpression has been shown to mediate oxidative stress-induced cell death (Lange et al., 2008) and alter expression of several ISR factors, including chaperones and the pro-apoptotic transcription factor C/EBP-homologous protein (CHOP) in neurons (Galehdar et al., 2010).”
BackgroundElucidation of brefeldin A-induced ER and Golgi stress responses in Neuro2a cells
Oh‐hashi, K., Hasegawa, T., Mizutani, Y., Takahashi, K., & Hirata, Y. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04187-1 · Cited by 22
Overexpression of CREB protein protects from tunicamycin-induced apoptosis in various rat cell types
Balogh, A., Németh, M., Koloszár, I., Markó, L., Przybył, Ł., Jinno, K., Szigeti, C., Heffer, M., Gebhardt, M., Szeberényi, J., et al. (2014) · APOPTOSIS · doi:10.1007/s10495-014-0986-z · Cited by 16
Peroxisomal import stress activates integrated stress response and inhibits ribosome biogenesis
Kim, J., Huang, K., Vo, P. T. T., Miao, T., Correia, J., Kumar, A., Simons, M. J. P., & Bai, H. (2024) · PNAS Nexus · doi:10.1093/pnasnexus/pgae429 · Cited by 13
“It is known that ATF4 responds to oxidative stress as a redox-regulated transcription factor (58 – 60).”
BackgroundDiabetic macular oedema: under‐represented in the genetic analysis of diabetic retinopathy
Broadgate, S., Kiire, C. A., Halford, S., & Chong, V. N. (2018) · Acta Ophthalmologica · doi:10.1111/aos.13678 · Cited by 15
“…CCL2 production is a major factor responsible for leucocyte migration and interaction with the endothelium resulting in microvascular injury of the retina (Jiang et al. 2007; Lange et al. 2008; Bouman et al. 2011; Chen et al. 2012; Suragani et al. 2012; Zhong et al. 2012; Huang et al. 2015).”
BackgroundÖrd, D., Örd, T., Biene, T., & Örd, T. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.08.003 · Cited by 17
“Trib3 expression in response to arsenite involved the transcription factor ATF4,which is known to be induced by ER stress and oxidative stress in general [15,68].”
BackgroundAlim, I., Haskew-Layton, R. E., Aleyasin, H., Guo, H., & Ratan, R. R. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-801415-8.00014-x · Cited by 18
Self-citationSims, S. G., & Meares, G. P. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00446 · Cited by 17
Stress-Free Evolution: The Nrf-Coordinated Oxidative Stress Response in Early Diverging Metazoans
Doonan, L. B., Hartigan, A., Okamura, B., & Long, P. F. (2019) · Integrative and Comparative Biology · doi:10.1093/icb/icz055 · Cited by 12
MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury
Rininger, A., DeJesus, C., Totten, A., Wayland, A., & Halterman, M. W. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.41 · Cited by 14
“Although it is not yet known whether stress-induced MKP-1 antagonizes the pro-survival function of C/EBPb in the injured adult nervous system, we found that loss of C/EBPb expression in hypoxic neurons promotes cell death in vitro,(12) suggesting the stoichiometric relationship between the available pool of bZIP heter…”
BackgroundRun, Ribosome, Run: From Compromised Translation to Human Health
Vind, A., Snieckute, G., Bekker‐Jensen, S., & Blasius, M. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0157 · Cited by 17
“While ISR and the GCN2 kinase mostly have protective effects, some data indicate a role for the phospho-eIF2 a / ATF4 axis in neuronal cell death, suggesting a differentiated response depending on the intensity and duration of stress conditions (Han et al., 2013; Lange et al., 2008).”
Abdel‐Ghaffar, A., El-Hossary, G. G., Mahmoud, A. M., Elshazly, A. H. M., Hassanin, O. A., Saleh, A., Mansour, S. M., Metwally, F. G., Hanafy, L. K., Karam, S. H., et al. (2021) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2021.1888302 · Cited by 14
Kim, H., Jang, Y., Ryu, J., Seo, D., Lee, S., Choi, S., Kim, D. H., Moh, S. H., & Shin, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713616 · Cited by 10
“ATF4 is a pivotal mediator in maintaining metabolic homeostasis and oxidative equilibrium [6].”
BackgroundMethodSteinberger, A. E., Tecos, M. E., Phelps, H. M., Rubin, D., Davidson, N., Guo, J., & Warner, B. (2022) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00302.2021 · Cited by 12
Signaling Overlap between the Golgi Stress Response and Cysteine Metabolism in Huntington’s Disease
Paul, B. (2021) · Antioxidants · doi:10.3390/antiox10091468 · Cited by 12
“ATF4 may have dual functions, modulating either cell survival or cell death, and excessive stimulation of ATF4 signaling may cause cell death [93].”
BackgroundErez, N., Hubel, E., Avraham, R., Cohen, R., Fishman, S., Bantel, H., Manns, M., Tirosh, B., Zvibel, I., & Shibolet, O. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx143 · Cited by 12
“CHOP, sXBP1 and the N-terminal portion of ATF6 accumulate in the nucleus following UPR induction (Lange et al., 2008; Marciniak et al., 2004).”
BackgroundLi, M., Xu, J.-Y., Du, K., Wang, G., Feng, Y.-T., & Liu, P.-F. (2025) · Free Radical Biology & Medicine · doi:10.1016/j.freeradbiomed.2025.06.020 · Cited by 11
Signaling plasticity in the integrated stress response
Boone, M., & Zappa, F. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1271141 · Cited by 14
Gao, Y., Wei, G. Z., Forston, M. D., Rood, B. R., Hodges, E. R., Burke, D. A., Andres, K. R., Morehouse, J. R., Armstrong, C., Glover, C., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-36258-2 · Cited by 12
Capatina, N., Burton, G., & Yung, H. (2022) · Physiological Reports · doi:10.14814/phy2.15467 · Cited by 11
“Furthermore, there was a significant increase (p = 0.0002) of nuclear Atf4 in TE cells of HCY- treated blastocysts (Figure 2d), indicating potential functional activity of the Atf4 transcription factor (Lange et al., 2008).”
BackgroundInfluentialRole of Activating Transcription Factor 4 in Murine Choroidal Neovascularization Model
Yasuda, H., Tanaka, M., Nishinaka, A., Nakamura, S., Shimazawa, M., & Hara, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168890 · Cited by 13
“ATF4 functions as a basic leucine zipper (bZIP) transcription factor, and it regulates the expression of some proteins to solve upstream stress conditions [18,19].”
BackgroundJDP2 is directly regulated by ATF4 and modulates TRAIL sensitivity by suppressing the ATF4–DR5 axis
Engler, M. J., Mimura, J., Yamazaki, S., & Itoh, K. (2020) · FEBS Open Bio · doi:10.1002/2211-5463.13017 · Cited by 11
Cross Talk Between p22phox and ATF4 in the Endothelial Unfolded Protein Response
Petry, A., Zhang, Z.-W., Trautz, B., Rieß, F., & Görlach, A. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7481 · Cited by 11
Characterization of V-ATPase inhibitor-induced secretion of cysteine-rich with EGF-like domains 2
Oh‐hashi, K., Kanamori, Y., Hirata, Y., & Kiuchi, K. (2014) · Cell Biology and Toxicology · doi:10.1007/s10565-014-9274-5 · Cited by 10
“A variety of ER stress-inducible genes have been identified and suggested to participate in the onset and progression of various diseases (e.g., neurodegenerative diseases and inflammations) (Lange et al. 2008; Woo et al. 2009).”
BackgroundSilencing ATF4 inhibits JMJD3‐dependent JUNB/ETS1 axis and mitigates cerebral ischemic injury
Wu, G., Zhang, X., Li, S., Wang, L.-N., Bai, J., Wang, H.-X., & Shu, Q. (2022) · Journal of biochemical and molecular toxicology · doi:10.1002/jbt.23070 · Cited by 10
Integrated Stress Response in Neuronal Pathology and in Health
Korneeva, N. L. (2022) · Biochemistry (Moscow) · doi:10.1134/s0006297922140103 · Cited by 14
“It was suggested that ATF4 serves as a pro death transcription factor that sensitizes neurons to oxidative stress [88].”
BackgroundInterleukin-15 modulates the response of cortical neurons to ischemia
Nguyen, V., Ameri, K., Huynh, K., Fredkin, M., Grona, R. J., Larpthaveesarp, A., Gonzalez, F. F., & Yeghiazarians, Y. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103658 · Cited by 8
Yousefian-Jazi, A., Kim, S., Chu, J., Choi, S.-H., Nguyen, P. T.-T., Park, U., Kim, M.-G., Hwang, H., Lee, K., Kim, Y., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00792-y · Cited by 9
“The minor allele (T/G) of rs304152 impaired ATF4 binding to MEF2C enhancer region, resulting a reduction of the transcriptional activity in its own gene expression [39].”
The endoplasmic reticulum participated in drug metabolic toxicity
Huang, Q., Chen, Y., Zhang, Z., Xue, Z., Hua, Z., Luo, X., Yang, L., Lu, C. C., Lü, A., & Liu, Y. (2022) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09689-8 · Cited by 9
Bocai, N. I., Marcora, M. S., Belfiori-Carrasco, L. F., Morelli, L., & Castaño, E. M. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-181021 · Cited by 12
Zhang, L., Guan, C., Wang, S., Pfeiffer, N., & Grus, F. (2025) · Antioxidants · doi:10.3390/antiox14030363 · Cited by 8
“Additionally, we examined the expression of activating transcription factor Additionally, we examined the expression of activating transcription factor 4 (ATF4), a key mediator in endoplasmic reticulum (ER) stress known to promote apoptosis and exacerbate neuronal damage [26].”
Ferenczi, S., Mógor, F., Takacs, P., Kovács, T., Tóth, V. É., Varga, Z. V., Kovács, K., Lohinai, Z., Vass, K. C., Nagy, N., et al. (2023) · Scientific Reports · doi:10.1038/s41598-023-50059-7 · Cited by 9
“It also was identified as one of the most prominent factors involved in neurodegeneration 50,51 , whereas Atf4 was reported as an unequivocally prodeath neuronal transcriptional factor, strongly implicated in Parkinson’s disease 52,53 , similarly to Egr1 54,55 .”
BackgroundExpression analysis and functional characterization of thioredoxin domain-containing protein 11
Murase, R., Yamamoto, A., Hirata, Y., & Oh-hashi, K. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07932-x · Cited by 8
“eIF2α phosphorylation leads to the shutdown of new protein synthesis, except for the induction of some ER stress-related factors [10, 15, 16].”
Background
Metadata
- Authors
- Lange, P. S., Chavez, J. C., Pinto, J. T., Coppola, G., Sun, C.-W., Townes, T. M., Geschwind, D. H., & Ratan, R. R.
- Affiliations
- University of Bonn (DE)
- Cornell University (US)
- New York Medical College (US)
- 6Program in Neurogenetics, Department of Neurology,
- University of Alabama at Birmingham (US)
- University of California, Los Angeles (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2008-05-05
- Volume
- 205
- Issue
- 5
- Pages
- 1227-1242
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2373852
- OpenAlex
- W2105818495
- Cited by
- 272
- References
- 62
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 17 · 2023: 19 · 2022: 17 · 2021: 21 · 2020: 12 · 2019: 18 · 2018: 19 · 2017: 9 · 2016: 17 · 2015: 17 · 2014: 20 · 2013: 16 · 2012: 13
- FWCI
- 3.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Touro Scholar (Touro College) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Heart Association
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Burke Foundation
- Deutsche Forschungsgemeinschaft
- Universität zu Köln
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS040591, NS40591)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- ATF4, oxidative stress, neuronal cell death, transcription factors, glutathione depletion, ischemic stroke, infarct size, redox regulation, bZIP transcription factors, neuroprotection, stroke recovery
- MeSH terms
- Animals, Cell Nucleus, Cell Survival, Cells, Cultured, Cerebral Cortex, Chromatin, DNA, Neurons, Plasmids, Polymerase Chain Reaction, Leucine Zippers, Cell Death, Mice, Knockout, Oxidative Stress, Mice, Activating Transcription Factor 4
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