Stub1 Acetylation by CBP/p300 Attenuates Chronic Hypoxic-Driven Pulmonary Hypertension by Suppressing HIF-2a

HIF-1/2 (Hypoxia-Inducible Factors 1/2) are fundamental to the development of pulmonary hypertension (PH). Prolonged hypoxia can trigger the shift from HIF-1 to HIF-2 activity, which is critical in PH progression. Ubiquitin ligases regulate HIF activity through protein degradation. However, little is known about if or how these ligases control the HIF-1/2 switch associated with PH progression. We demonstrate that Stub1 (STIP1 homology and U-box containing protein1), an E3 ubiquitin ligase, influences HIF response to hypoxia by suppressing HIF-2 and enhancing HIF-1 mRNA, protein stability, and activity. Stub1 transgenic mice exposed to prolonged hypoxia exhibited significant decreases in pulmonary vessel and right ventricular remodeling, resulting from a failure of chronic hypoxia to trigger the transition from HIF-1a to HIF-2a and activate HIF-2a. Specifically, acute hypoxia induced the acetylation of Stub1 at lysine 287, promoting its translocation into the nucleus and selectively suppressing HIF-2 activity. Despite the decreased total Stub1 expression, the marginal increase in Stub1^K287Ac in the nucleus was sufficient for suppressing chronic hypoxia-induced HIF-2 activity in Stub1 transgenic mice. Our findings established that Stub1 acetylation regulates the putative HIF-1/2a switch driving PH progression in hypoxic and pseudohypoxic conditions.