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

TitleCleavage of serum response factor mediated by enteroviral protease 2A contributes to impaired cardiac function.
Publication TypeJournal Article
Year of Publication2012
AuthorsWong, J, Zhang, J, Yanagawa, B, Luo, Z, Yang, X, Chang, J, McManus, B, Luo, H
JournalCell Research
Volume22
Issue2
Pagination360-71
Date Published2012 Feb
ISSN1748-7838
KeywordsAmino Acid Sequence, Animals, Cardiomyopathy, Dilated, Caspase Inhibitors, Caspases, Cell Line, Enterovirus, Gene Expression, Heart, HeLa Cells, Humans, Male, Mice, MicroRNAs, Molecular Sequence Data, Mutagenesis, Site-Directed, Myocytes, Cardiac, Peptide Hydrolases, Protein Structure, Tertiary, Serum Response Factor, Viral Proteins, Virus Replication
Abstract

Enteroviral infection can lead to dilated cardiomyopathy (DCM), which is a major cause of cardiovascular mortality 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 expression 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 downregulation 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 transactivation domain from DNA-binding domain, resulting in the disruption of SRF-mediated gene transactivation. In addition 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.

DOI10.1038/cr.2011.114
Alternate JournalCell Res.
PubMed ID21769134
PubMed Central IDPMC3271589
Grant List79921-1 / / Canadian Institutes of Health Research / Canada
97749-1 / / Canadian Institutes of Health Research / Canada
K02 HL098956 / HL / NHLBI NIH HHS / United States
K02 HL098956-02 / HL / NHLBI NIH HHS / United States
K0202HL098956 / HL / NHLBI NIH HHS / United States
R01 HL102314 / HL / NHLBI NIH HHS / United States
R01 HL102314-02 / HL / NHLBI NIH HHS / United States
R01HL102314 / HL / NHLBI NIH HHS / United States
R21 HL094844 / HL / NHLBI NIH HHS / United States
R21 HL094844-02 / HL / NHLBI NIH HHS / United States
R21HL094844 / HL / NHLBI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada