{"doi":"10.1101/2020.03.12.989061","title":"Hypoxic response regulators RHY-1 and EGL-9/PHD promote longevity through a VHL-1 independent transcriptional response","abstract":"Abstract HIF-1-mediated adaptation to changes in oxygen availability is a critical aspect of healthy physiology. HIF is regulated by a conserved mechanism whereby EGLN/PHD family members hydroxylate HIF in an oxygen-dependent manner, targeting it for ubiquitination by Von-Hippel-Lindau (VHL) family members, leading to its proteasomal degradation. The activity of the only C. elegans PHD family member, EGL-9, is also regulated by a hydrogen sulfide sensing cysteine-synthetase-like protein, CYSL-1, which is, in turn, regulated by RHY-1/acyltransferase. Over the last decade multiple seminal studies have established a role for the hypoxic response in regulating longevity, with mutations in vhl-1 substantially extending C. elegans lifespan through a HIF-1-dependent mechanism. However, studies on other components of the hypoxic signaling pathway that similarly stabilize HIF-1 have shown more mixed results, suggesting that mutations in egl-9 and rhy-1 frequently fail to extend lifespan. Here, we show that egl-9 and rhy-1 mutants suppress the long-lived phenotype of vhl-1 mutants. We also show that RNAi of rhy-1 extends lifespan of wild-type worms while decreasing lifespan of vhl-1 mutant worms. We further identify VHL-1-independent gene expression changes mediated by EGL-9 and RHY-1 and find that a subset of these genes contributes to longevity regulation. The resulting data suggest that changes in HIF-1 activity derived by interactions with EGL-9 likely contribute greatly to its role in regulation of longevity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129170,"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":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277699,"name":"Hillary Miller","orcid":"0000-0002-8204-7990","position":1,"is_corresponding":false},{"id":387611,"name":"Megan L. Schaller","orcid":"0000-0003-4347-8701","position":2,"is_corresponding":false},{"id":389251,"name":"Abrielle Fretz","orcid":null,"position":3,"is_corresponding":false},{"id":387613,"name":"Marshall Howington","orcid":"0000-0002-8697-4441","position":4,"is_corresponding":false},{"id":387614,"name":"Marjana Sarker","orcid":"0000-0001-6766-6737","position":5,"is_corresponding":false},{"id":387619,"name":"Shijiao Huang","orcid":"0000-0003-1867-4794","position":6,"is_corresponding":false},{"id":277701,"name":"Scott F. Leiser","orcid":"0000-0002-8003-2955","position":7,"is_corresponding":false},{"id":339577,"name":"Joseph Kruempel","orcid":"0000-0001-6541-7104","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","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":[]}