A conserved antioxidant defense at the endoplasmic reticulum membrane

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.