1. Desmosomal COP9 regulates proteome degradation in arrhythmogenic right ventricular dysplasia/cardiomyopathy
- Author
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Liang, Yan, Lyon, Robert C, Pellman, Jason, Bradford, William H, Lange, Stephan, Bogomolovas, Julius, Dalton, Nancy D, Gu, Yusu, Bobar, Marcus, Lee, Mong-Hong, Iwakuma, Tomoo, Nigam, Vishal, Asimaki, Angeliki, Scheinman, Melvin, Peterson, Kirk L, and Sheikh, Farah
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cardiovascular ,Heart Disease ,Rare Diseases ,Biotechnology ,Genetics ,2.1 Biological and endogenous factors ,Adaptor Proteins ,Signal Transducing ,Animals ,Arrhythmogenic Right Ventricular Dysplasia ,COP9 Signalosome Complex ,Desmosomes ,Disease Models ,Animal ,Female ,Humans ,Male ,Mice ,Mice ,Knockout ,Proteolysis ,Proteome ,Cardiology ,Muscle Biology ,Ubiquitin-proteosome system ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
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.
- Published
- 2021