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bioRxiv · 10.1101/2024.06.19.599784

ER-GUARD: an evolutionarily conserved antioxidant defense system at ER membranes

Ji, Z.·Pandey, T.·Belly, H. d.·Wang, B.·Weiner, O. K.·Tang, Y.·Guang, S.·Goddard, T.·Ma, D. K.
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Abstract

Oxidative protein folding in the endoplasmic reticulum (ER) is essential for all eukaryotic cells yet generates hydrogen peroxide (H2O2), a reactive oxygen species (ROS). The ER-transmembrane protein that provides reducing equivalents to ER and guards the cytosol for antioxidant defense remains unidentified. Here we combine AlphaFold2-based and functional reporter screens in C. elegans to discover a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles. Deleting C. elegans ERGU-1 causes excessive H2O2 and transcriptional gene up-regulation through SKN-1, homolog of mammalian antioxidant master regulator NRF2. ERGU-1 deficiency also impairs organismal reproduction and behavioral responses to H2O2. Both C. elegans and human ERGU-1 proteins localize to ER membranes and form network reticulum structures. Human and Drosophila homologs of ERGU-1 can rescue C. elegans mutant phenotypes, demonstrating evolutionarily ancient and conserved functions. In addition, purified ERGU-1 and human homolog TMEM161B exhibit redox-modulated oligomeric states. Together, our results reveal an ER-membrane-specific protein machinery for peroxide detoxification and suggest a previously unknown and conserved mechanisms for antioxidant defense in animal cells.

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Ji, Z., Pandey, T., Belly, H. d., Wang, B., Weiner, O. K., Tang, Y., Guang, S., Goddard, T., Ma, D. K.. 2024-06-20. ER-GUARD: an evolutionarily conserved antioxidant defense system at ER membranes. https://doi.org/10.1101/2024.06.19.599784

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