OTUB1 augments hypoxia signaling via its non-canonical ubiquitination inhibition of HIF-1α during hypoxia adaptation.

As a main regulator of cellular responses to hypoxia, the protein stability of hypoxia-inducible factor (HIF)-1α is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1α protein stability as well as its activity can be further regulated under hypoxia is not well understood. In this study, we found that OTUB1 augments hypoxia signaling independent of PHDs/VHL and FIH. OTUB1 binds to HIF-1α and depletion of OTUB1 reduces endogenous HIF-1α protein under hypoxia. In addition, OTUB1 inhibits K48-linked polyubiquitination of HIF-1α via its non-canonical inhibition of ubiquitination activity. Furthermore, OTUB1 promotes hypoxia-induced glycolytic reprogramming for cellular metabolic adaptation. These findings define a novel regulation of HIF-1α under hypoxia and demonstrate that OTUB1-mediated HIF-1α stabilization positively regulates HIF-1α transcriptional activity and benefits cellular hypoxia adaptation.