Amanda Czerwinski, Paul Sidlowski, Emily Mooers, Yong Liu, Ru-Jeng Teng, Kirkwood Pritchard Jr., Xigang Jing, Suresh Kumar, Amy Y. Pan, Pengyuan Liu, Girija G. Konduri, Adeleye Afolayan
Medical College of Wisconsin. University of Arizona College of Medicine.
United States
American Journal of Respiratory Cell and Molecular Biology
Am J Respir Cell Mol Biol 2025;
DOI: 10.1165/rcmb.2024-0353OC
Abstract
Hypoxia-inducible factors (HIF-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 STIP1 homology and U-box containing protein1 (Stub1), 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-1α to HIF-2α and activate HIF-2α. 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 deceased total Stub1 expression, the marginal increase in Stub1K287Ac levels was sufficient for suppressing chronic hypoxia-induced HIF-2 activity in Stub1 transgenic mice. Our findings established that Stub1 acetylation regulates the putative HIF-1/2α switch driving PH progression in hypoxic and pseudohypoxic conditions.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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