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Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFAT signaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions.

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. [ABSTRACT FROM AUTHOR]