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The COP9 signalosome as a novel mediator of arrhythmogenic cardiomyopathy (404.1)
Author(s) -
Lyon Robert,
Mezzano Valeria,
Pellman Jason,
Lim ByungKwan,
Iwakuma Tomoo,
Lee MongHong,
Nigam Vishal,
Scheinman Melvin,
Sheikh Farah
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.404.1
Subject(s) - desmoplakin , biology , microbiology and biotechnology , gene knockdown , protein degradation , cancer research , genetics , gene
Arrhythmogenic cardiomyopathy (AC) is a genetic‐based heart disease characterized by a high frequency of ventricular arrhythmias leading to sudden cardiac death in young people. AC is termed a cardiac disease of the desmosome; however, only 40% of AC patients carry genetic mutations in known desmosomal cell‐cell junction genes, suggesting that novel mechanisms remain to be uncovered. To address this challenge, we set out to identify novel desmosomal associated proteins by performing a yeast‐two‐hybrid screen with the desmosomal gene, desmoplakin (DSP), as bait in an adult human heart cDNA library. We identified COP9 signalosome subunit 6 (CSN6), a protein traditionally linked to mediating ubiquitin‐mediated protein degradation, as a novel desmosomal (DSP)‐interacting protein, which localizes at the intercalated disc in both adult mouse and human heart. We show that CSN6 levels are dramatically reduced at the intercalated disc in hearts of a mouse model of AC (cardiac‐specific DSP knockout mice (DSP‐cKO)) and human AC patient harboring desmosomal mutations in DSP and plakophilin‐2 (PKP2). Yeast‐two‐hybrid assays revealed that the DSP mutation in the human AC patient abrogates the binding of DSP with CSN6. We further show that DSP‐cKO hearts display underlying defects in protein degradation associated with loss of CSN6 function including increased neddylation, ubiquitination, and ubiquitin‐mediated autophagy profiles. A striking increase in markers for the autophagy/lysosome degradation system could also be detected specifically at the intercalated disc in DSP‐cKO mouse hearts. Most importantly, analysis of CSN6 heterozygous knockout mouse hearts and CSN6 knockdown in neonatal ventricular cardiomyocytes in vitro revealed that loss of CSN6 is sufficient to trigger and recapitulate the desmosomal and protein turnover defects observed in our mouse model of AC. Our studies highlight the importance of CSN6 at the cardiac desmosome and reveal new mechanisms underlying AC. Grant Funding Source : Supported by American Heart Association