Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy

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 uncover a cardiac COP9 desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricts neddylation and targets desmosomal proteome degradation. Pharmacological restoration of CSN enzymatic function (via neddylation inhibitors) can rescue desmosomal protein loss in CSN6 deficient cardiomyocytes. We further show that disruption of CSN6‐mediated (neddylation) pathways underlie ARVD/C as CSN6 binding, localization, levels and function are impacted in hearts of classic ARVD/C mouse models and ARVD/C patients impacted by desmosomal loss and mutations, respectively. Through the generation of two novel models, we show that cardiomyocyte‐restricted CSN6 loss in mice selectively accelerates desmosomal destruction and dysfunction to trigger classic disease features associated with ARVD/C. Through the generation of a novel mouse model harboring a desmosomal point mutation, we show that human desmosomal mutations destablize CSN6 and are also sufficient to trigger ARVD/C in mice. We identify a desmosomal resident regulatory complex that restricts desmosomal proteome degradation and disease. We anticipate our findings have broad implications towards understanding mechanisms driving desmosome degradation in other desmosomal‐based diseases, such as cancers. Since neddylation inhibitors are in clinical trials to treat certain cancers, our studies also provide new insights on sub‐cellular and protein targets of neddylation.