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)-1 alpha is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1 alpha 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-1 alpha and depletion of OTUB1 reduces endogenous HIF-1 alpha protein under hypoxia. In addition, OTUB1 inhibits K48-linked polyubiquitination of HIF-1 alpha 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-1 alpha under hypoxia and demonstrate that OTUB1-mediated HIF-1 alpha stabilization positively regulates HIF-1 alpha transcriptional activity and benefits cellular hypoxia adaptation.