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

Abstract

AbstractOxidative 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 inC. elegansto identify a previously uncharacterized and evolutionarily conserved protein ERGU-1 that fulfills these roles.DeletingC. elegansERGU-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 behaviors. BothC. elegansand human ERGU-1 proteins localize to ER membranes and form network reticulum structures. We name this system ER-GUARD,EndoplasmicReticulumGuardianAegis ofRedoxDefense. Human andDrosophilahomologs of ERGU-1 can rescueC. elegansmutant phenotypes, demonstrating evolutionarily ancient and conserved functions. Together, our results reveal an ER-membrane-specific protein machinery and defense-net system ER-GUARD for peroxide detoxification and suggest a previously unknown but conserved pathway for antioxidant defense in animal cells.