GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases

Zheyan Fang; Gang Zhao; Shuang Zhao; Xueting Yu; Runyang Feng; You-En Zhang; Haomin Li; Lei Huang; Zhenyang Guo; Zhentao Zhang; Mukaddas Abdurahman; Hangnan Hong; Peng Li; Bing Wu; Jinhang Zhu; Xin Zhong; Dong Huang; Hao Lu; Xin Zhao; Zhaoyang Chen; Wenbin Zhang; Junjie Guo; Hongchao Zheng; Yue He; Shengying Qin; Haojie Lu; Yun Zhao; Xiangdong Wang; Junbo Ge; Hua Li

doi:10.1016/j.xinn.2024.100565

GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases

Innovation (Camb). 2024 Jan 8;5(2):100565. doi: 10.1016/j.xinn.2024.100565. eCollection 2024 Mar 4.

Authors

Zheyan Fang¹, Gang Zhao², Shuang Zhao³, Xueting Yu¹, Runyang Feng¹, You-En Zhang⁴, Haomin Li⁵, Lei Huang⁶, Zhenyang Guo¹, Zhentao Zhang¹, Mukaddas Abdurahman¹, Hangnan Hong¹, Peng Li¹, Bing Wu⁴, Jinhang Zhu⁷, Xin Zhong², Dong Huang², Hao Lu², Xin Zhao², Zhaoyang Chen⁸, Wenbin Zhang⁹, Junjie Guo¹⁰, Hongchao Zheng¹¹, Yue He¹², Shengying Qin⁷, Haojie Lu¹³, Yun Zhao^{14

15

16}, Xiangdong Wang¹⁷, Junbo Ge^{1

2

18

19

20

21

22}, Hua Li¹

Affiliations

¹ Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.
² Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Department of Medical Examination, Shanghai Xuhui District Central Hospital, Shanghai 200031, China.
⁴ Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan 442000, China.
⁵ Clinical Data Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
⁶ Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
⁷ Bio-X Institute, Key Laboratory for The Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai 200030, China.
⁸ Department of Cardiology, Heart Center of Fujian Province, Fujian Medical University Union Hospital, Fuzhou 350001, China.
⁹ Department of Cardiology, Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, Hangzhou 310020, China.
¹⁰ Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
¹¹ Department of Cardiology, Shanghai Xuhui District Central Hospital, Shanghai 200031, China.
¹² Department of Cardiology, Shanghai Eighth People's Hospital, Shanghai 200235, China.
¹³ Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
¹⁴ State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
¹⁵ School of Life Science and Technology, Shanghai Tech University, 100 Haike Road, Shanghai 201210, China.
¹⁶ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
¹⁷ Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China.
¹⁸ State Key Laboratory of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
¹⁹ National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
²⁰ Shanghai Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
²¹ Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai 200032, China.
²² Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai 200032, China.

Abstract

Partial endothelial-to-mesenchymal transition (EndMT) is an intermediate phenotype observed in endothelial cells (ECs) undergoing a transition toward a mesenchymal state to support neovascularization during (patho)physiological angiogenesis. Here, we investigated the occurrence of partial EndMT in ECs under hypoxic/ischemic conditions and identified general transcription factor IIH subunit 4 (GTF2H4) as a positive regulator of this process. In addition, we discovered that GTF2H4 collaborates with its target protein excision repair cross-complementation group 3 (ERCC3) to co-regulate partial EndMT. Furthermore, by using phosphorylation proteomics and site-directed mutagenesis, we demonstrated that GTF2H4 was involved in the phosphorylation of receptor coactivator 3 (NCOA3) at serine 1330, which promoted the interaction between NCOA3 and p65, resulting in the transcriptional activation of NF-κB and the NF-κB/Snail signaling axis during partial EndMT. In vivo experiments confirmed that GTF2H4 significantly promoted partial EndMT and angiogenesis after ischemic injury. Collectively, our findings reveal that targeting GTF2H4 is promising for tissue repair and offers potential opportunities for treating hypoxic/ischemic diseases.