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

The Innovation > 2024 Vol. 5 > No. 2

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

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

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²³These authors contributed equally
Corresponding authors: ge.junbo@zs-hospital.sh.cn (J.G.); lihua199988@hotmail.com (H.L.)
Received Date: February 19, 2023

Accepted Date: January 01, 2024

Published Online: January 08, 2024

The Innovation 5(2), https://doi.org/10.1016/j.xinn.2024.100565 | Cite this article

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GRAPHICAL ABSTRACT

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. ■ Partial endothelial-to-mesenchymal transition (EndMT) helps create new blood vessels and repair tissues after a lack of blood flow.
2. ■ GTF2H4 works together with ERCC3 to encourage partial EndMT through the NCOA3/NF-κB/Snail pathway.
3. ■ Targeting endothelial GTF2H4 could be a hopeful treatment for diseases caused by insufficient blood supply.

ABSTRACT

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.

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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. GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases[J]. The Innovation, 2024, 5(2). https://doi.org/10.1016/j.xinn.2024.100565

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. GTF2H4 regulates partial EndMT via NF-κB activation through NCOA3 phosphorylation in ischemic diseases[J]. The Innovation, 2024, 5(2). https://doi.org/10.1016/j.xinn.2024.100565

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

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