Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination

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 GSK3 beta markedly enhanced NFATc4 ubiquitination and decreased its transactivation, whereas inhibition of GSK3 beta had opposite effects. Importantly, ubiquitination and phosphorylation induced by GSK3 beta 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.