Integrated Stress Response Modulates Cellular Redox State via Induction of Cystathionine γ-Lyase
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The integrated stress response mediated by eukaryotic translation initiation factor 2α (eIF2α) phosphorylation maintains cellular homeostasis under endoplasmic reticulum (ER) stress. eIF2α phosphorylation induces activating transcription factor 4 (ATF4), a basic leucine zipper transcription factor that regulates the expression of genes responsible for amino acid metabolism, cellular redox state, and anti-stress responses. Cystathionine γ-lyase (CSE) and cystathionine β-synthase are critical enzymes in the transsulfuration pathway, which also regulate cellular redox status by modulating glutathione (GSH) levels. To determine the link between the integrated stress response and the transsulfuration pathway, we used homocysteine (Hcy) as an inducer of eIF2α phosphorylation and ATF4 gene induction. Mouse embryonic fibroblasts (MEFs) lacking ATF4 (ATF4(-/-)) had reduced GSH levels and increased reactive oxygen species and were susceptible to apoptotic cell death under normal culture conditions. Further, ATF4(-/-) MEFs were more sensitive to Hcy-induced cytotoxicity and showed significantly reduced intracellular GSH levels associated with apoptosis. ATF4(-/-) MEFs could be rescued from l-Hcy-induced apoptosis by β-mercaptoethanol medium supplementation that increases cysteine levels and restores GSH synthesis. ATF4(-/-) MEFs showed little or no CSE protein but did express cystathionine β-synthase. Further, ER stress-inducing agents, including tunicamycin and thapsigargin, induced the expression of CSE in ATF4(+/+) MEFs. Consistent with ATF4(-/-) MEFs, CSE(-/-) MEFs showed significantly greater apoptosis when treated with tunicamycin, thapsigargin, and l-Hcy, compared with CSE(+/+) MEFs. Liver and kidney GSH levels were also reduced in CSE(-/-) mice, suggesting that CSE is a critical factor in GSH synthesis and may act to protect the liver and kidney from a variety of conditions that cause ER stress.
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Expression of CSE is induced by the UPR through the PERK pathway and ATF4.
“It is notable that expression of CSE is induced by the UPR through the PERK pathway and ATF4 (146), illustrating crosstalk between these pathways.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [146]
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Placental Origins of Chronic Disease
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- Authors
- Dickhout, J. G., Carlisle, R. E., Jerome, D. E., Mohammed-Ali, Z., Jiang, H., Yang, G., Mani, S., Garg, S. K., Banerjee, R., Kaufman, R. J., Maclean, K. N., Wang, R., & Austin, R. C.
- Affiliations
- St. Joseph’s Healthcare Hamilton (CA)
- University of Colorado Anschutz (US)
- Lakehead University (CA)
- University of Michigan (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Austin, Richard C.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 287
- Issue
- 10
- Pages
- 7603-7614
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3293561
- OpenAlex
- W1968439134
- Cited by
- 129
- References
- 65
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 10 · 2023: 11 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 13 · 2015: 10 · 2014: 12 · 2013: 10 · 2012: 4
- FWCI
- 5.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Heart and Stroke Foundation of Canada
- National Institutes of Health
- Amgen Canada
- Canadian Institutes of Health Research (74477, 86708_1, MOP-74477)
- National Heart, Lung, and Blood Institute (HL58984, R01HL052173, P01HL057346, R01HL058984)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, R37DK042394)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- integrated stress response, eIF2α phosphorylation, ATF4, cystathionine gamma-lyase, cystathionine beta-synthase, transsulfuration pathway, glutathione synthesis, cellular redox state, endoplasmic reticulum stress, homocysteine, reactive oxygen species, apoptosis, tunicamycin, thapsigargin, cysteine, liver, kidney
- MeSH terms
- Animals, Cells, Cultured, Cystathionine gamma-Lyase, Embryo, Mammalian, Fibroblasts, Glutathione, Homocysteine, Kidney, Liver, Lyases, Oxidation-Reduction, Sulfhydryl Compounds, Apoptosis, Mice, Knockout, Mice, Activating Transcription Factor 4, Endoplasmic Reticulum Stress
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