An oxygen-insensitive Hif-3α isoform inhibits Wnt signaling by destabilizing the nuclear β-catenin complex

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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.

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Peng Zhang

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Yan Bai

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Ling Lu

Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, China

Competing interests
The authors declare that no competing interests exist.
Yun Li

Key Laboratory of Marine Drugs, Ministry of Education and School of Medicine and Pharmacy, Ocean University of China, Qingdao, China

Competing interests
The authors declare that no competing interests exist.
Cunming Duan

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

For correspondence
cduan@umich.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#09707) of the University of Michigan. Every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.