{"doi":"10.7554/elife.83373","title":"Z-REX uncovers a bifurcation in function of Keap1 paralogs","abstract":"Studying electrophile signaling is marred by difficulties in parsing changes in pathway flux attributable to on-target, vis-à-vis off-target, modifications. By combining bolus dosing, knockdown, and Z-REX—a tool investigating on-target/on-pathway electrophile signaling, we document that electrophile labeling of one zebrafish-Keap1-paralog (zKeap1b) stimulates Nrf2- driven antioxidant response (AR) signaling (like the human-ortholog). Conversely, zKeap1a is a dominant-negative regulator of electrophile-promoted Nrf2-signaling, and itself is nonpermissive for electrophile-induced Nrf2-upregulation. This behavior is recapitulated in human cells: (1) zKeap1b-expressing cells are permissive for augmented AR-signaling through reduced zKeap1b–Nrf2 binding following whole-cell electrophile treatment; (2) zKeap1a-expressing cells are non-permissive for AR-upregulation, as zKeap1a–Nrf2 binding capacity remains unaltered upon whole-cell electrophile exposure; (3) 1:1 ZKeap1a:zKeap1b-co-expressing cells show no Nrf2-release from the Keap1-complex following whole-cell electrophile administration, rendering these cells unable to upregulate AR. We identified a zKeap1a-specific point-mutation (C273I) responsible for zKeap1a’s behavior during electrophilic stress. Human-Keap1(C273I), of known diminished Nrf2-regulatory capacity, dominantly muted electrophile-induced Nrf2-signaling. These studies highlight divergent and interdependent electrophile signaling behaviors, despite conserved electrophile sensing .","journal":"eLife","year":2022,"id":262530,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":573966,"name":"Jesse R. Poganik","orcid":"0000-0003-3098-8550","position":1,"is_corresponding":false},{"id":671072,"name":"Kuan‐Ting Huang","orcid":"0000-0001-7057-1448","position":2,"is_corresponding":false},{"id":644023,"name":"Saba Parvez","orcid":"0000-0001-8608-1494","position":3,"is_corresponding":false},{"id":375758,"name":"Yi Zhao","orcid":"0000-0002-6049-1943","position":4,"is_corresponding":false},{"id":301896,"name":"Hongyu Lin","orcid":"0000-0002-5675-8537","position":5,"is_corresponding":false},{"id":699024,"name":"Xuyu Liu","orcid":"0000-0003-4096-3090","position":6,"is_corresponding":false},{"id":375757,"name":"Marcus J. C. Long","orcid":"0000-0002-0343-9671","position":7,"is_corresponding":false},{"id":375759,"name":"Yimon Aye","orcid":"0000-0002-1256-4159","position":8,"is_corresponding":false},{"id":573967,"name":"Alexandra Van Hall‐Beauvais","orcid":"0000-0003-2515-5191","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T00:26:25.074177Z","pmid":"36300632","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":[]}