{"doi":"10.1101/2024.06.19.599784","title":"AlphaFold2-Guided Functional Screens Reveal a Conserved Antioxidant Protein at ER Membranes","abstract":"Abstract Oxidative protein folding in the endoplasmic reticulum (ER) is essential for all eukaryotic cells yet generates hydrogen peroxide (H 2 O 2 ), 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 H 2 O 2 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 H 2 O 2 . 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":498629,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":871103,"name":"Taruna Pandey","orcid":"0000-0001-7278-6434","position":1,"is_corresponding":false},{"id":986309,"name":"Henry De Belly","orcid":"0000-0003-2452-4450","position":2,"is_corresponding":false},{"id":1345571,"name":"Jingxuan Yao","orcid":null,"position":3,"is_corresponding":false},{"id":577094,"name":"Bingying Wang","orcid":"0000-0001-7362-7371","position":4,"is_corresponding":false},{"id":656841,"name":"Orion D. Weiner","orcid":"0000-0002-1778-6543","position":5,"is_corresponding":false},{"id":232218,"name":"Yao Tang","orcid":"0000-0002-0492-1902","position":6,"is_corresponding":false},{"id":572372,"name":"Shouhong Guang","orcid":"0000-0001-7700-9634","position":7,"is_corresponding":false},{"id":1345275,"name":"Simin Xu","orcid":"0000-0001-6839-9642","position":8,"is_corresponding":false},{"id":1345276,"name":"Zhiyong Lou","orcid":"0000-0003-2728-881X","position":9,"is_corresponding":false},{"id":30001,"name":"Thomas D. Goddard","orcid":null,"position":10,"is_corresponding":false},{"id":142695,"name":"Dengke K. Ma","orcid":"0000-0002-5619-7485","position":11,"is_corresponding":false},{"id":1345570,"name":"Zhijian Ji","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:09:42.181447Z","pmid":"38948723","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}