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 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.

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Kardiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Cardiac and Cardiovascular Systems hsv//eng
nedd8-activating enzyme-inhibitor
ubiquitin-proteasome system
crystal-structure
cardiomyopathy
gene
signalosome
cardiomyocytes
organization
variants
families
Research & Experimental Medicine

Lyon, R. C. (author)
Pellman, J. (author)
Bradford, W. H. (author)
Lange, StephanGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Centre for Molecular and Translational Medicine,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xlstez (author)
Bogomolovas, J. (author)
Dalton, N. D. (author)
Gu, Y. S. (author)
Bobar, M. (author)
Lee, M. H. (author)
Iwakuma, T. (author)
Nigam, V. (author)
Asimaki, A. (author)
Scheinman, M. (author)
Peterson, K. L. (author)
Sheikh, F. (author)
Göteborgs universitetInstitutionen för medicin, avdelningen för molekylär och klinisk medicin (creator_code:org_t)

In:Journal of Clinical Investigation: American Society for Clinical Investigation131:110021-97381558-8238

By the author/editor: Liang, Y.; Lyon, R. C.; Pellman, J.; Bradford, W. H.; Lange, Stephan; Bogomolovas, J.; show more...; Dalton, N. D.; Gu, Y. S.; Bobar, M.; Lee, M. H.; Iwakuma, T.; Nigam, V.; Asimaki, A.; Scheinman, M.; Peterson, K. L.; Sheikh, F.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cardiac and Card ...

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