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

Date Published: April 10, 2014

Publisher: Public Library of Science

Author(s): Xin Ye, Huifang Mary Zhang, Ye Qiu, Paul J. Hanson, Maged Gomaa Hemida, Wei Wei, Pamela A. Hoodless, Fanny Chu, Decheng Yang, Jay A. Nelson.

http://doi.org/10.1371/journal.ppat.1004070

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.

Partial Text

microRNAs (miRNAs) are endogenous gene regulators functioning through targeting messenger RNAs (mRNAs) [1]. Their capability of targeting several genes simultaneously enables their vast involvement in physiological and pathological conditions [2], including cardiac dysfunctions and viral infections [3], [4]. Among these small RNAs, miR-21 is one of the most essential ones due to its wide involvement in development and diseases [5].

miRNAs are among the pivotal regulators of virus-host interactions. Several studies have reported the role of host miRNAs in regulating the replication of CVB3 and the activation of inflammatory process [18]–[20], [22]. However, the research on the roles of miRNAs in cardiomyocyte pathology during the occurrence of viral myocarditis, particularly the regulation of cell-cell connections which are fundamental to cardiac structures and functions, is still missing. This study is the first to reveal the role of miR-21 in modulating ICDs in the cardiomyocytes during CVB3 infection. We identified two new targets, YOD1 and VCL, of miR-21. Suppression of YOD1 by miR-21 promoted desmin degradation and desmosome disorganization. Targeting VCL by miR-21 directly triggered the reduction and disorientation of fascia adherens components including pan-cadherin and α-E-catenin. These findings provide a new perspective to understand the role of miRNAs in viral myocarditis.

 

Source:

http://doi.org/10.1371/journal.ppat.1004070

 

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