Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy

Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17570-5. doi: 10.1073/pnas.1420196111. Epub 2014 Nov 24.

Abstract

Misfolded proteins are an emerging hallmark of cardiac diseases. Although some misfolded proteins, such as desmin, are associated with mutations in the genes encoding these disease-associated proteins, little is known regarding more general mechanisms that contribute to the generation of misfolded proteins in the heart. Reduced translational fidelity, caused by a hypomorphic mutation in the editing domain of alanyl-tRNA synthetase (AlaRS), resulted in accumulation of misfolded proteins in specific mouse neurons. By further genetic modulation of the editing activity of AlaRS, we generated mouse models with broader phenotypes, the severity of which was directly related to the degree of compromised editing. Severe disruption of the editing activity of AlaRS caused embryonic lethality, whereas an intermediate reduction in AlaRS editing efficacy resulted in ubiquitinated protein aggregates and mitochondrial defects in cardiomyocytes that were accompanied by progressive cardiac fibrosis and dysfunction. In addition, autophagic vacuoles accumulated in mutant cardiomyocytes, suggesting that autophagy is insufficient to eliminate misfolded proteins. These findings demonstrate that the pathological consequences of diminished tRNA synthetase editing activity, and thus translational infidelity, are dependent on the cell type and the extent of editing disruption, and provide a previously unidentified mechanism underlying cardiac proteinopathy.

Keywords: cardiomyopathy; mistranslation; protein misfolding; protein quality control; translational fidelity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine-tRNA Ligase / deficiency*
  • Alanine-tRNA Ligase / genetics*
  • Alleles
  • Animals
  • Bacterial Proteins / genetics
  • Echocardiography
  • Heart Diseases / genetics*
  • Homeostasis
  • Humans
  • Hydrolysis
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Models, Molecular
  • Mutation
  • Myocytes, Cardiac / ultrastructure
  • Paraffin / chemistry
  • Protein Binding
  • Protein Folding
  • Protein Structure, Tertiary
  • Proteostasis Deficiencies / genetics*
  • RNA Editing*

Substances

  • Bacterial Proteins
  • Paraffin
  • Alanine-tRNA Ligase