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A conserved antioxidant defense at the endoplasmic reticulum membrane.

Zhijian Ji·Henry de Belly·Taruna Pandey·Bingying Wang·Yao Tang·Jingxuan Yao·Shiya Xu·Kathy Li·Yanchang Bian·Shouhong Guang·Zhiyong Lou·Al Burlingame·Orion D Weiner·Thomas D Goddard·Dengke K Ma
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Abstract

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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AnimalsEndoplasmic ReticulumCaenorhabditis elegansHumansHydrogen PeroxideCaenorhabditis elegans ProteinsAntioxidantsMembrane ProteinsIntracellular MembranesOxidation-ReductionAlphaFold2CP: molecular biologyER membrane proteostasisER redox homeostasisERGU-1SKN-1/NRF2 signalingTMEM161Bantioxidant defenseconserved transmembrane oxidoreductasehydrogen peroxideoxidative protein foldingJournal Article

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Zhijian Ji, Henry de Belly, Taruna Pandey, Bingying Wang, Yao Tang, Jingxuan Yao, Shiya Xu, Kathy Li, Yanchang Bian, Shouhong Guang, Zhiyong Lou, Al Burlingame, Orion D Weiner, Thomas D Goddard, Dengke K Ma. 2026-06-04. A conserved antioxidant defense at the endoplasmic reticulum membrane.. https://doi.org/10.1016/j.celrep.2026.117489

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