Details

Autor(en) / Beteiligte

• Wong, Jerry
• Zhang, Jingchun
• Yanagawa, Bobby
• Luo, Zongshu
• Yang, Xiangsheng
• Chang, Jiang
• McManus, Bruce
• Luo, Honglin

Titel

Cleavage of serum response factor mediated by enteroviral protease 2A contributes to impaired cardiac function

Ist Teil von

• Cell research, 2012-02, Vol.22 (2), p.360-371

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Enteroviral infection can lead to dilated cardiomyopathy （DCM）, which is a major cause of cardiovascular mortal- ity worldwide. However, the pathogenetic mechanisms have not been fully elucidated. Serum response factor （SRF） is a cardiac-enriched transcription regulator controlling the expression of a variety of target genes, including those involved in the contractile apparatus and immediate early response, as well as microRNAs that silence the expres- sion of cardiac regulatory factors. Knockout of SRF in the heart results in downregulation of cardiac contractile gene expression and development of DCM. The goal of this study is to understand the role of SRF in enterovirus-induced cardiac dysfunction and progression to DCM. Here we report that SRF is cleaved following enteroviral infection of mouse heart and cultured cardiomyocytes. This cleavage is accompanied by impaired cardiac function and downreg- ulation of cardiac-specific contractile and regulatory genes. Further investigation by antibody epitope mapping and site-directed mutagenesis demonstrates that SRF cleavage occurs at the region of its transactivation domain through the action of virus-encoded protease 2A. Moreover, we demonstrate that cleavage of SRF dissociates its transactiva- tion domain from DNA-binding domain, resulting in the disruption of SRF-mediated gene transactivation. In addi- tion to loss of functional SRF, finally we report that the N-terminal fragment of SRF cleavage products can also act as a dominant-negative transcription factor, which likely competes with the native SRF for DNA binding. Our results suggest a mechanism by which virus infection impairs heart function and may offer a new therapeutic strategy to ameliorate myocardial damage and progression to DCM.