{"doi":"10.1165/rcmb.2024-0353oc","title":"Stub1 Acetylation by CBP/p300 Attenuates Chronic Hypoxic-Driven Pulmonary Hypertension by Suppressing HIF-2α","abstract":"Abstract HIF-1/2 (Hypoxia-Inducible Factors 1/2) are fundamental to the development of pulmonary hypertension (PH). Prolonged hypoxia can trigger the shift from HIF-1 to HIF-2 activity, which is critical in PH progression. Ubiquitin ligases regulate HIF activity through protein degradation. However, little is known about if or how these ligases control the HIF-1/2 switch associated with PH progression. We demonstrate that Stub1 (STIP1 homology and U-box containing protein1), an E3 ubiquitin ligase, influences HIF response to hypoxia by suppressing HIF-2 and enhancing HIF-1 mRNA, protein stability, and activity. Stub1 transgenic mice exposed to prolonged hypoxia exhibited significant decreases in pulmonary vessel and right ventricular remodeling, resulting from a failure of chronic hypoxia to trigger the transition from HIF-1α to HIF-2α and activate HIF-2α. Specifically, acute hypoxia induced the acetylation of Stub1 at lysine 287, promoting its translocation into the nucleus and selectively suppressing HIF-2 activity. Despite the decreased total Stub1 expression, the marginal increase in Stub1K287Ac in the nucleus was sufficient for suppressing chronic hypoxia-induced HIF-2 activity in Stub1 transgenic mice. Our findings established that Stub1 acetylation regulates the putative HIF-1/2α switch driving PH progression in hypoxic and pseudohypoxic conditions.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2025,"id":516501,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":927038,"name":"Paul Sidlowski","orcid":"0000-0001-5501-6737","position":1,"is_corresponding":false},{"id":1381818,"name":"Emily A. Mooers","orcid":"0000-0001-6207-4601","position":2,"is_corresponding":false},{"id":1381819,"name":"Yong Liu","orcid":"0000-0001-6932-583X","position":3,"is_corresponding":false},{"id":720663,"name":"Ru‐Jeng Teng","orcid":"0000-0003-4321-2452","position":4,"is_corresponding":false},{"id":927402,"name":"Kirkwood Pritchard","orcid":null,"position":5,"is_corresponding":false},{"id":721357,"name":"Xigang Jing","orcid":null,"position":6,"is_corresponding":false},{"id":808261,"name":"Suresh Kumar","orcid":"0000-0002-1945-0621","position":7,"is_corresponding":false},{"id":444935,"name":"Amy Pan","orcid":"0000-0002-7199-7704","position":8,"is_corresponding":false},{"id":898543,"name":"Pengyuan Liu","orcid":"0000-0002-6251-0415","position":9,"is_corresponding":false},{"id":720665,"name":"Girija G. Konduri","orcid":"0000-0002-3602-1538","position":10,"is_corresponding":false},{"id":927039,"name":"Adeleye J. Afolayan","orcid":"0000-0001-9886-6694","position":11,"is_corresponding":false},{"id":927401,"name":"Amanda Czerwinski","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40019849","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":[]}