Abstract 20108: A Newly Identified Interaction Between Desmoplakin and COP9 Signalsome Subunit 6 Reveals a New Mechanism Underlying Sudden Death
Arrrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic based cardiomyopathy, characterized by ventricular dysfunction, fibrofatty replacement of the ventricle and ventricular arrhythmias leading to sudden cardiac death in young people. ARVC is termed a “disease of the desmosome"; however, limited information exists on how desmosomal protein dysregulation/loss triggers ARVC. To identify novel desmosomal proteins and mechanisms underlying ARVC, we performed a yeast-two-hybrid screen using the desmosomal gene, desmoplakin (DSP) as bait to screen an adult human heart cDNA library. We identified COP9 signalosome subunit 6 (CSN6) as a novel DSP-interacting protein, localizing at the intercalated disc (ICD) in both adult mouse and human heart. Well-known functions of CSN are to regulate protein degradation via ubiquitination; however, the role of CSN6 in the heart and ARVC has not been defined. We show that CSN6 levels are dramatically reduced at the ICD in a mouse model of ARVC (cardiac-specific DSP knockout mice (DSP-cKO)) and a human ARVC patient harboring DSP and plakophilin-2 mutations. Yeast-two-hybrid assays revealed that the DSP mutation in the ARVC patient specifically abrogated binding of DSP to CSN6. DSP-cKO hearts also displayed underlying protein degradation defects associated with loss of CSN6, including a striking accumulation of autophagy markers and autophagosomes at the ICD. Importantly, generation of novel cardiac-specific CSN6 knockout models using the a-myosin heavy chain(MHC)-Cre (CSN6-cKO) and a-MHC-MerCreMer (CSN6-iKO) mouse lines revealed that loss of CSN6 in mice was sufficient to elicit premature death, which was associated with early ventricular depolarization delay and a biventricular form of cardiomyopathy, reminiscent of ARVC. Ultrastructurally, CSN6-iKO hearts displayed loss of cardiac architecture associated with an accumulation of autophagosomes at the ICD, similar to our mouse model of ARVC. At the molecular level, CSN6-iKO hearts exhibited early loss of DSP (prior to heart dysfunction) and recapitulated the protein degradation defects observed in our mouse model of ARVC. We highlight the importance of CSN6 at the cardiac desmosome and reveal new mechanisms underlying ARVC and sudden death.
Author Disclosures: Y. Liang: None. R. Lyon: None. J. Pellman: None. V. Mezzano: None. Y. Gu: None. N. Dalton: None. M. Lee: None. T. Iwakuma: None. V. Nigam: None. K. Peterson: None. F. Sheikh: None.
- © 2016 by American Heart Association, Inc.