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Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
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Journal Article
Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
2021
Overview
Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication, as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here, we uncovered a cardiac constitutive photomorphogenesis 9 (COP9) desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels, and function were affected in hearts of classic mouse and human models of ARVD/C affected by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to junctional reduction/loss of CSN6 and human desmosomal mutations destabilizing junctional CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
Publisher
American Society for Clinical Investigation
Subject
Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ Animals
/ Arrhythmogenic Right Ventricular Dysplasia - genetics
/ Arrhythmogenic Right Ventricular Dysplasia - metabolism
/ Cardiology and Cardiovascular Disease
/ COP9 Signalosome Complex - genetics
/ COP9 Signalosome Complex - metabolism
/ Disease
/ families
/ Female
/ gene
/ Heart
/ Humans
/ Kardiologi och kardiovaskulära sjukdomar
/ Male
/ Mice
/ Mutation
/ nedd8-activating enzyme-inhibitor
/ Proteins
/ Research & Experimental Medicine
/ Roles
/ variants
