Zebrafish usp3 loss promotes hypoxic tolerance by disrupting deubiquitination of K63-polyubiquitinated hif-1αa

The hypoxia-inducible factor (HIF)-mediated hypoxia signaling pathway influences oxygen homeostasis in aerobic organisms. This pathway is regulated by several other pathways. Elucidation of its regulation and the underlying mechanisms may provide insights into the strategies of adaptation and tolerance of organisms to hypoxia. In this study, we found that loss of ubiquitin-specific protease 3 (usp3) in zebrafish promotes hypoxia tolerance. Zebrafish usp3 specifically binds to hif-1αa and induces its proteasomal degradation, which is dependent on its deubiquitinase activity. This process leads to the suppression of hypoxia signaling under hypoxia. In addition, usp3 catalyzes the deubiquitination of K63-polyubiquitinated hif-1αa. Endogenous evidence indicated that mammalian USP3 behaves like zebrafish usp3 in regulating the activity of HIF-1α. These findings revealed a novel role for usp3 in influencing hypoxia signaling and showed that usp3-mediated HIF-1α degradation impairs hypoxia signaling, leading to a decrease in hypoxia tolerance.