Cardiomyocyte-specific activation of the sarcomere-localized Dnajb6b chaperone causes cardiomyopathy and heart failure through upregulated sarcoplasmic reticulum stress

Abstract

Aims

Despite abundant expression of DNAJB6 gene in the heart, its roles in cardiac diseases remain underexplored. We aimed to investigate the function of its zebrafish (Danio rerio) ortholog, the dnajb6b gene, in cardiomyopathy and heart failure.

Materials and methods

Both loss-of-function mutation and gain-of-function transgenic approaches were employed in zebrafish. High frequency echocardiography was performed to evaluate cardiac function indices in adult zebrafish. 4-phenylbutyric acid (4-PBA) was used to pharmacologically inhibit sarcoplasmic reticulum (SR) stress in zebrafish. Western blot was carried out to determine expression of DNAJB6 isoforms in human patients' heart tissues.

Key findings

Global loss-of-function mutations affecting both the sarcomere-localized short (Dnajb6b[S]) and nucleus-localized long (Dnajb6b[L]) isoforms appeared phenotypically normal. In contrast, cardiomyocyte-specific overexpression of a truncated, sarcomere-localized Dnajb6b(L) isoform (Dnajb6b[∆L]) led to severe cardiomyopathy and heart failure phenotypes. Mechanistically, Dnajb6b responded to sarcoplasmic reticulum (SR) stress and activation of Dnajb6b(∆L) resulted in elevated SR stress, accumulation of ubiquitinated protein aggregation, and aberrant activation of autophagy. 4-PBA treatment partially rescued cardiac dysfunction and extended the lifespan of zebrafish with cardiomyocyte-specific activation of Dnajb6b(∆L). Finally, elevated expression of both DNAJB6(S) and DNAJB6(L) isoforms was detected in failing human hearts, supporting their clinical relevance.

Significance

Gain-of-function mutation in Dnajb6b(∆L) isoform causes cardiomyopathy and heart failure, likely mediated by elevated SR stress. This study enhances our understanding of Dnajb6's role in cardiac proteostasis and highlights its potential as a therapeutic target for the treatment of cardiomyopathy and heart failure.