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

SUBMITTER: Zhang P 

PROVIDER: S-EPMC4769163 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature