The COP9 signalosome subunit 8 (CSN8) hypomorphism impairs deneddylation and exacerbates desmin‐related cardiomyopathy (DRC)

Abstract

BackgroundInadequate protein quality control (PQC) contributes to the development of cardiac diseases. We previously identified the COP9 signalosome (CSN), a deneddylase that removes ubiquitin‐like protein Nedd8 from target proteins, is essential to proteasomal and autophagic proteolysis in the heart. The present study determines the impact of CSN8 hypomorphism (CSN8hypo) on the removal of misfolded proteins in mouse hearts.Methods and resultsCSN8hypo accumulated the neddylated forms of cullins and non‐cullin proteins in mouse hearts. Using a proteasome functional reporter mouse, we found the proteasomal function was compromised in CSN8hypo mouse hearts. When crossed with transgenic mice overexpressing CryABR120G, a bona fide misfolded protein, CSN8hypo reduced ubiquitinated proteins but increased protein aggregates in the heart, which eventually aggravated the CryABR120G‐induced cardiomyopathy and shortened the lifespan of the mice. In cultured cardiomyocytes, CSN8 knockdown suppressed the ubiquitination and degradation of CryABR120G, leading to accumulation of protein aggregates and exacerbation of CryABR120G‐mediated proteotoxicity.ConclusionThe CSN is required for the ubiquitination and clearance of misfolded proteins in cardiomyocytes, and therefore is critical to cardiac PQC. (Funding agencies: NIH and AHA)