Stub1 Acetylation by CBP/p300 Attenuates Chronic Hypoxic-Driven Pulmonary Hypertension by Suppressing HIF-2α. Am J Respir Cell Mol Biol 2025 Sep;73(3):369-382
Date
02/28/2025Pubmed ID
40019849Pubmed Central ID
PMC12416312DOI
10.1165/rcmb.2024-0353OCScopus ID
2-s2.0-105016502039 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
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-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 decreased total Stub1 expression, the marginal increase in Stub1K287Ac 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-1/2α switch driving PH progression in hypoxic and pseudohypoxic conditions.
Author List
Czerwinski A, Sidlowski P, Mooers E, Liu Y, Teng RJ, Pritchard K Jr, Jing X, Kumar S, Pan AY, Liu P, Konduri GG, Afolayan AJAuthors
Adeleye James Afolayan MD Associate Professor in the Pediatrics department at Medical College of WisconsinSuresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Emily A. Mooers MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Amy Y. Pan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AcetylationAnimals
Chronic Disease
Humans
Hypertension, Pulmonary
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Mice, Inbred C57BL
Mice, Transgenic
Transcription Factors
Ubiquitin-Protein Ligases
Vascular Remodeling
p300-CBP Transcription Factors
