Ribosomal Protein SA (RPSA) is required for localized translation and sarcomere maintenance

Abstract

SummaryCardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and the significance of localized translation are unknown. Using proximity labeling, we identified Ribosomal Protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, the loss of RPSA led to impaired local protein translation and reduced sarcomere integrity. By employing CAS9 expressing mice along with adeno-associated viruses expressing CRE recombinase and single-guide RNAs targetingRpsa, we knocked out RPSA in vivo and observed mis-localization of ribosomes and diminished local translation. These genetic mosaic mice with RPSA knockout in a subset of cardiomyocytes developed dilated cardiomyopathy, featuring atrophy of RPSA-deficient cardiomyocytes, compensatory hypertrophy of unaffected cardiomyocytes, left ventricular dilation, and impaired contractile function. We demonstrate that RPSA C-terminal domain is sufficient for localization to the Z-lines. These findings highlight RPSA as a ribosomal factor responsible for ribosome localization to the Z-line, facilitating local translation and sarcomere maintenance.