Endoplasmic reticulum (ER) stress–induced reactive oxygen species (ROS) are detrimental for the fitness of a thioredoxin reductase mutant
Open accessAbstract
The unfolded protein response (UPR) is constitutively active in yeast thioredoxin reductase mutants, suggesting a link between cytoplasmic thiol redox control and endoplasmic reticulum (ER) oxidative protein folding. The unique oxidative environment of the ER lumen requires tight regulatory control, and we show that the active UPR depends on the presence of oxidized thioredoxins rather than arising because of a loss of thioredoxin function. Preventing activation of the UPR by deletion of HAC1 , encoding the UPR transcription factor, rescues a number of thioredoxin reductase mutant phenotypes, including slow growth, shortened longevity, and oxidation of the cytoplasmic GSH pool. This is because the constitutive UPR in a thioredoxin reductase mutant results in the generation of hydrogen peroxide. The oxidation of thioredoxins in a thioredoxin reductase mutant requires aerobic metabolism and the presence of the Tsa1 and Tsa2 peroxiredoxins, indicating that a complete cytoplasmic thioredoxin system is crucial for maintaining ER redox homeostasis.
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The ER produces ROS, oxidizing proteins like thioredoxins and causing ER stress.
“The ER produces ROS, oxidizing proteins like thioredoxins and causing ER stress18.”
From Impairing the interaction between Erg11 and cytochrome P450 reductase Ncp1 enhances azoles’ antifungal activities (2025) · cites this paper as [18]
The Discussion identifies the ER as a source of ROS, but describes the proposed sequence in the opposite direction: oxidized thioredoxins can activate the unfolded protein response (UPR), and ER-derived ROS can result as a side effect of that response. It does not support the claim that ER-produced ROS oxidize thioredoxins and thereby cause ER stress. (LLM, conf=0.88)
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References 76 · Cited by 36
- Authors
- Kritsiligkou, P., Rand, J. D., Weids, A. J., Wang, X., Kershaw, C. J., & Grant, C. M.
- Affiliations
- University of Manchester (GB)
- Corresponding author
- Grant, Chris M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 293
- Issue
- 31
- Pages
- 11984-11995
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6078444
- OpenAlex
- W2886442396
- Cited by
- 36
- References
- 76
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 2
- FWCI
- 1.96
- 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)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Funders
- RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/M020770/1, BB/P005594/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- endoplasmic reticulum stress, unfolded protein response, thioredoxin reductase, reactive oxygen species, hydrogen peroxide, HAC1, peroxiredoxin, Tsa1, glutathione oxidation, oxidative protein folding, yeast, aging, growth fitness
- MeSH terms
- Endoplasmic Reticulum, Glutathione, Hydrogen Peroxide, Mutation, Oxidation-Reduction, Peroxidases, Repressor Proteins, Saccharomyces cerevisiae, Thioredoxins, Thioredoxin-Disulfide Reductase, Signal Transduction, Gene Expression Regulation, Fungal, Protein Folding, Oxidative Stress, Saccharomyces cerevisiae Proteins, Basic-Leucine Zipper Transcription Factors, Genetic Fitness, Unfolded Protein Response, Endoplasmic Reticulum Stress
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