TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Guoxing Zheng; Changying Jiang; Yulin LI; Dandan Yang; Youcai MA; Bing Zhang; Xuan LI; Pei Zhang; Xiaoyu HU; Xueqiang Zhao; Jie DU; Xin Lin

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TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Author: Guoxing ZHENG ¹ ; Changying JIANG ² ; Yulin LI ³ ; Dandan YANG ⁴ ; Youcai MA ³ ; Bing ZHANG ⁴ ; Xuan LI ⁴ ; Pei ZHANG ⁴ ; Xiaoyu HU ⁴ ; Xueqiang ZHAO ⁴ ; Jie DU ³ ; Xin LIN ⁵
Author Information

1. Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, 100084, China. opqsky@126.com.
2. Department of Molecular and Cellular Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA.
3. Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing, 100029, China.
4. Institute for Immunology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China.
5. Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, 100084, China. linxin307@tsinghua.edu.cn.
Publication Type:Journal Article
Keywords: ARVD; NF-κB; TGFβ; TMEM43; fibrosis; knock-in mouse
From: Protein & Cell 2019;10(2):104-119
CountryChina
Language:English
Abstract: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor κB (NF-κB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF-κB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFβ1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-κB-TGFβ signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development.