title: An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex.
abstract: Hypoxia-inducible factors (HIFs), while best known for their roles in the hypoxic response, have oxygen-independent roles in early development with poorly defined mechanisms. Here, we report a novel Hif-3α variant, Hif-3α2, in zebrafish. Hif-3α2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3α2 is a nuclear protein with significant hypoxia response element (HRE)-dependent transcriptional activity. Hif-3α2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3α2 by CRISPR/Cas9 genome editing increases, while Hif-3α2 overexpression decreases, Wnt/β-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3α2 binds to β-catenin and destabilizes the nuclear β-catenin complex. This mechanism is distinct from GSK3β-mediated β-catenin degradation and is conserved in humans. These findings provide new insights into the oxygen-independent actions of HIFs and uncover a novel mechanism regulating Wnt/β-catenin signaling.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States.
authors.forename: Cunming
authors.identifier: http://orcid.org/0000-0001-6794-2762
authors.initials: C
authors.lastname: Duan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D010100:Oxygen / Q000032:analysis; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D060449:Wnt Signaling Pathway; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D010100:Oxygen; D020033:Protein Isoforms; D051176:beta Catenin
keywords: Wnt signaling; developmental biology; hypoxia; stem cells; zebrafish