Genetic Inhibition Of Cullin-Based Ubiquitin Ligase Dynamics In Adult Mouse Hearts Suffices To Cause Heart Failure (Hf)

BACKGROUND: The COP9 signalosome (CSN) is an evolutionarily conserved protein complex formed by 8 subunits (CSN1 ~ CSN8). By deneddylating cullins (Cul), CSN regulates the dynamics of Cul-based E3s, a large family of ubiquitin ligases. The ubiquitin-proteasome system (UPS) degrades most cellular proteins. UPS malfunction in the heart is implicated in HF genesis but a causative relationship has not been established yet. METHODS & RESULTS: We achieved cardiomyocyte-restricted knockout of the Csn8 gene (CR-KO) in adult mice, using the Cre-loxP system with a tamoxifen-inducible modified Cre. Cardiac CSN8 protein nearly disappeared by 5 days after CR-KO induction. CR-KO increased the protein levels of neddylated Cul1 and Cul4a, p62/sequestosome 1, and the lipidated form of LC3 (LC3-II). Electron microscopy reveals marked ultrastructure changes: myofibril alignment disruption, mitochondrial degeneration, and massive autophagic vacuoles in CR-KO myocytes. Echocardiography shows progressive left ventricular (LV) wall thinning and marked declines in LV ejection fraction and fraction shortening. Significantly reduced cardiac contractility and relaxation were also detected by LV hemodynamics. All CR-KO mice died within 8 days after CR-KO induction. CONCLUSIONS: CSN8 is required for CSN activities and for maintaining cardiac structure and function in adult mice. UPS impairment suffices to cause HF.