Int J Biol Sci 2020; 16(14):2727-2740. doi:10.7150/ijbs.48437


E3 Ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease

Ying Zhang1, Hao Qian1, Boquan Wu1, Shilong You1, Shaojun Wu1, Saien Lu1, Pingyuan Wang2, Liu Cao3✉, Naijin Zhang1✉, Yingxian Sun1✉

1. Department of Cardiology, the First Hospital of China Medical University, Shenyang, Liaoning, P.R. China.
2. Staff scientist, Center for Molecular Medicine National Heart Lung and Blood Institute, National Institutes of Health, the United States.
3. Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University; Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning, China.

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Zhang Y, Qian H, Wu B, You S, Wu S, Lu S, Wang P, Cao L, Zhang N, Sun Y. E3 Ubiquitin ligase NEDD4 family‑regulatory network in cardiovascular disease. Int J Biol Sci 2020; 16(14):2727-2740. doi:10.7150/ijbs.48437. Available from

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Protein ubiquitination represents a critical modification occurring after translation. E3 ligase catalyzes the covalent binding of ubiquitin to the protein substrate, which could be degraded. Ubiquitination as an important protein post-translational modification is closely related to cardiovascular disease. The NEDD4 family, belonging to HECT class of E3 ubiquitin ligases can recognize different substrate proteins, including PTEN, ENaC, Nav1.5, SMAD2, PARP1, Septin4, ALK1, SERCA2a, TGFβR3 and so on, via the WW domain to catalyze ubiquitination, thus participating in multiple cardiovascular-related disease such as hypertension, arrhythmia, myocardial infarction, heart failure, cardiotoxicity, cardiac hypertrophy, myocardial fibrosis, cardiac remodeling, atherosclerosis, pulmonary hypertension and heart valve disease. However, there is currently no review comprehensively clarifying the important role of NEDD4 family proteins in the cardiovascular system. Therefore, the present review summarized recent studies about NEDD4 family members in cardiovascular disease, providing novel insights into the prevention and treatment of cardiovascular disease. In addition, assessing transgenic animals and performing gene silencing would further identify the ubiquitination targets of NEDD4. NEDD4 quantification in clinical samples would also constitute an important method for determining NEDD4 significance in cardiovascular disease.

Keywords: NEDD4 E3 ligases, post translation modification, ubiquitin proteasome system, cardiovascular disease