Coxsackieviral Infection Causes Cytoplasmic Aggregation and Cleavage of TAR DNA Binding Protein‐43

Abstract

Coxsackievirus B3 (CVB3) is a positive single‐stranded enterovirus that infects the heart. CVB3 infection can cause myocarditis and lead to dilated cardiomyopathy (DCM). In North America, DCM accounts for approximately 20% of heart failure and sudden death in children and young adults. Recent findings have shown similar molecular pathologies between cardiomyopathies and neurodegenerative diseases. In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, insoluble‐cytoplasmic TAR DNA binding protein‐43 (TDP‐43)‐aggregates are a common biomarker contributing directly to pathological disease progression. The importance of insoluble protein aggregates in viral pathogenesis has also been recognized, resembling that of neurodegenerative diseases. However, the significance of TDP‐43 in CVB3‐induced cardiomyopathy remains unstudied.In this study, we investigated the interplay between CVB3 and TDP‐43 using A/J mice, a strain susceptible to virus‐induced cardiomyopathy, and HeLa cell culture models. Our studies demonstrated that CVB3 infection leads to redistribution of nuclear TDP‐43 into cytoplasmic aggregates in a viral protease 2A dependent manner. We also found that viral protease 3C, actively cleaves TDP‐43 at amino acid 327 into two respective cleavage fragments. The respective N‐terminal cleavage fragment inhibited native TDP43 activity in the nucleus as a transcriptional regulator. We conclude that TDP‐43 pathologies in CVB3‐induced cardiomyopathy may be similar to those previously found in neurodegenerative diseases.This work was supported by the Canadian Institutes of Health Research (HL)