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Peer-reviewedCC BY 4.0Cell reports

A conserved antioxidant defense at the endoplasmic reticulum membrane

  • Zhijian Ji1
  • Henry de Belly1,2
  • Taruna Pandey1
  • Bingying Wang1
  • Yao Tang3
  • Jingxuan Yao4
  • Shiya Xu4
  • Kathy Li5
  • Yanchang Bian1
  • Shouhong Guang3
  • Zhiyong Lou4
  • Al Burlingame5
3 more authors
  • Orion D. Weiner1,2
  • Thomas D. Goddard5
  • Dengke K. Ma1,6,7,8
8 affiliations
  1. 1Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
  2. 2Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
  3. 3School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
  4. 4MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China
  5. 5Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA
  6. 6Department of Physiology, University of California San Francisco, San Francisco, CA, USA
  7. 7Innovative Genomics Institute, Berkeley, CA, USA
  8. 8Lead contact
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Abstract

SUMMARY: Oxidative protein folding in the endoplasmic reticulum (ER) is essential for eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species. The ER-transmembrane protein that supports ER proteostasis and guards the cytosol for antioxidant defense remains unidentified. Here, we combine AlphaFold2 and functional screens in C. elegans to discover a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting ERGU-1 upregulates H2O2 and NRF2/SKN-1-dependent gene expression. ERGU-1 deficiency also impairs organismal reproduction and behavioral responses to H2O2. Both C. elegans ERGU-1 and human homolog TMEM161B localize to ER membranes, forming reticular networks. Human and Drosophila homologs of ERGU-1 rescue C. elegans mutant phenotypes, demonstrating ancient and conserved functions. In addition, purified ERGU-1 and TMEM161B exhibit redox-modulated oligomeric states. Together, our results reveal an ER-membrane-specific machinery, suggesting a conserved mechanism for maintaining ER redox homeostasis and proteostasis in animal cells.

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Cite

BibTeXRIS
BibTeX
@article{ji2026conserved,
  title = {{A conserved antioxidant defense at the endoplasmic reticulum membrane}},
  author = {Zhijian Ji and Henry de Belly and Taruna Pandey and Bingying Wang and Yao Tang and Jingxuan Yao and Shiya Xu and Kathy Li and Yanchang Bian and Shouhong Guang and Zhiyong Lou and Al Burlingame and Orion D. Weiner and Thomas D. Goddard and Dengke K. Ma},
  journal = {Cell reports},
  year = {2026},
  month = jun,
  doi = {10.1016/j.celrep.2026.117489},
  url = {https://doi.org/10.1016/j.celrep.2026.117489},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A conserved antioxidant defense at the endoplasmic reticulum membrane
AU  - Zhijian Ji
AU  - Henry de Belly
AU  - Taruna Pandey
AU  - Bingying Wang
AU  - Yao Tang
AU  - Jingxuan Yao
AU  - Shiya Xu
AU  - Kathy Li
AU  - Yanchang Bian
AU  - Shouhong Guang
AU  - Zhiyong Lou
AU  - Al Burlingame
AU  - Orion D. Weiner
AU  - Thomas D. Goddard
AU  - Dengke K. Ma
PY  - 2026
DA  - 2026/06/04
JO  - Cell reports
DO  - 10.1016/j.celrep.2026.117489
UR  - https://doi.org/10.1016/j.celrep.2026.117489
AB  - SUMMARY: Oxidative protein folding in the endoplasmic reticulum (ER) is essential for eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species. The ER-transmembrane protein that supports ER proteostasis and guards the cytosol for antioxidant defense remains unidentified. Here, we combine AlphaFold2 and functional screens in C. elegans to discover a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting ERGU-1 upregulates H2O2 and NRF2/SKN-1-dependent gene expression. ERGU-1 deficiency also impairs organismal reproduction and behavioral responses to H2O2. Both C. elegans ERGU-1 and human homolog TMEM161B localize to ER membranes, forming reticular networks. Human and Drosophila homologs of ERGU-1 rescue C. elegans mutant phenotypes, demonstrating ancient and conserved functions. In addition, purified ERGU-1 and TMEM161B exhibit redox-modulated oligomeric states. Together, our results reveal an ER-membrane-specific machinery, suggesting a conserved mechanism for maintaining ER redox homeostasis and proteostasis in animal cells.
SN  - 2211-1247
ER  -