Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination

Fan, Yongna; Xie, Ping; Zhang, Tianpeng; Zhang, Hua; Gu, Dongfeng; She, Mingpeng; Li, Huihua

doi:10.1016/j.febslet.2008.11.009

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Volume 582, Issue 29 , Pages 4008-4014, 10 December 2008

Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination

Edited by Noboru Mizushima

Yongna Fan
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
Ping Xie
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
Tianpeng Zhang
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
Hua Zhang
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
Dongfeng Gu
- Division of Population Genetics and Prevention, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
Mingpeng She
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
Huihua Li
- Department of Pathology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, #5 Dong Dan San Tiao, Beijing 100005, China
- Corresponding author. Fax: +86 10 6529 6494.

Received 16 September 2008; received in revised form 20 October 2008; accepted 5 November 2008. published online 19 November 2008.

Abstract

Nuclear factor of activated T cells (NFATc4) has been implicated as a critical regulator of the cardiac development and hypertrophy. However, the mechanisms for regulating NFATc4 stability and transactivation remain unclear. We showed that NFATc4 protein was predominantly ubiquitinated through the formation of Lysine 48-linked polyubiquitin chains, and this modification decreased NFATc4 protein levels and its transcriptional activity. Furthermore, activation of GSK3β markedly enhanced NFATc4 ubiquitination and decreased its transactivation, whereas inhibition of GSK3β had opposite effects. Importantly, ubiquitination and phosphorylation induced by GSK3β repressed NFATc4-dependent cardiac-specific gene expression. These results demonstrate that the ubiquitin–proteasome system plays an important role in regulating NFATc4 stability and transactivation.