Coxsackievirus-Induced miR-21 Disrupts Cardiomyocyte Interactions via the Downregulation of Intercalated Disk Components

Abstract

Intercalated disks (ICDs) are substantial connections maintaining cardiac structures and mediating signal communications among cardiomyocytes. Deficiency in ICD components such as desmosomes, fascia adherens and gap junctions leads to heart dysfunction. Coxsackievirus B3 (CVB3) infection induces cardiac failure but its pathogenic effect on ICDs is unclear. Here we show that CVB3-induced miR-21 expression affects ICD structure, i.e., upregulated miR-21 targets YOD1, a deubiquitinating enzyme, to enhance the K48-linked ubiquitination and degradation of desmin, resulting in disruption of desmosomes. Inhibition of miR-21 preserves desmin during CVB3 infection. Treatment with proteasome inhibitors blocks miR-21-mediated desmin degradation. Transfection of miR-21 or knockdown of YOD1 triggers co-localization of desmin with proteasomes. We also identified K108 and K406 as important sites for desmin ubiquintination and degradation. In addition, miR-21 directly targets vinculin, leading to disturbed fascia adherens evidenced by the suppression and disorientation of pan-cadherin and α-E-catenin proteins, two fascia adherens-components. Our findings suggest a new mechanism of miR-21 in modulating cell-cell interactions of cardiomyocytes during CVB3 infection.

Author Summary

Coxsackievirus B3 (CVB3) is one of most common causes of heart inflammation and failure. However, the mechanism by which CVB3 induces cardiac damage has not been fully elucidated. Particularly, the involvement of microRNAs (miRNAs), a family of small RNAs controlling the progression of a wide range of diseases, in CVB3 infection is still unclear. These small RNAs are essential to understand the CVB3-caused heart muscle cell injury and have great potential to serve therapeutic purposes. Here, we systematically analyzed the miRNA changes during CVB3 infection and found that miR-21 is increased by viral infection. We further demonstrated that the CVB3-induced miR-21 triggers heart muscle cell damage by interfering with the cell-cell interactions. miR-21 suppresses the levels of components in cell-cell interactions by either promoting the degradation of those proteins or directly inhibiting the protein production. Inhibition of miR-21 can reduce the host injury caused by CVB3 infection. Our findings will shed new lights on the pathogenesis of CVB3-induced heart failure.