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

作者：Zhang, Peng; Bai, Yan; Lu, Ling; Li, Yun; Duan, Cunming^*

来源：eLife, 2016, 5: e08996.

DOI：10.7554/eLife.08996

• HYPOXIA-INDUCIBLE FACTOR
• RENAL-CELL-CARCINOMA
• LEFT-RIGHT ASYMMETRY
• GENE-EXPRESSION
• KUPFFERS VESICLE
• TRANSCRIPTION FACTOR
• NEGATIVE REGULATOR
• IN-VIVO
• C-CBL
• ZEBRAFISH

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-3 alpha variant, Hif-3 alpha 2, in zebrafish. Hif-3 alpha 2 lacks the bHLH, PAS, PAC, and ODD domains, and is expressed in embryonic and adult tissues independently of oxygen availability. Hif-3 alpha 2 is a nuclear protein with significant hypoxia response element (HRE)-dependent transcriptional activity. Hif-3 alpha 2 overexpression not only decreases embryonic growth and developmental timing but also causes left-right asymmetry defects. Genetic deletion of Hif-3 alpha 2 by CRISPR/Cas9 genome editing increases, while Hif-3 alpha 2 overexpression decreases, Wnt/beta-catenin signaling. This action is independent of its HRE-dependent transcriptional activity. Mechanistically, Hif-3 alpha 2 binds to beta-catenin and destabilizes the nuclear p-catenin complex. This mechanism is distinct from GSK3 beta-mediated beta-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/beta-catenin signaling.

• 出版日期2016-1-14
• 单位中国海洋大学