{"doi":"10.1101/2022.02.03.479044","title":"SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance","abstract":"SUMMARY The deleterious potential to generate oxidative stress and damage is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and physiological consequences of this remain unknown. To explore this connection, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":305783,"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":0.9604,"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":1000126,"name":"Talha F Siddiqi","orcid":null,"position":1,"is_corresponding":false},{"id":334737,"name":"Theodore Bolas","orcid":"0000-0003-3641-7898","position":2,"is_corresponding":false},{"id":258496,"name":"Raz Bar‐Ziv","orcid":"0000-0003-2615-1942","position":3,"is_corresponding":false},{"id":258498,"name":"Holly K. Gildea","orcid":"0000-0002-9549-890X","position":4,"is_corresponding":false},{"id":752124,"name":"Hanlin Zhang","orcid":"0000-0001-9353-6071","position":5,"is_corresponding":false},{"id":329543,"name":"Ryo Higuchi‐Sanabria","orcid":"0000-0001-8936-5812","position":6,"is_corresponding":false},{"id":258501,"name":"Andrew Dillin","orcid":"0000-0002-7427-2629","position":7,"is_corresponding":false},{"id":334738,"name":"Phillip A. Frankino","orcid":"0000-0002-3909-3422","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:32:44.983506Z","pmid":null,"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":[]}