title: Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy.
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.
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Satz
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: My-Nuong
authors.initials: MN
authors.lastname: Vo
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Nangle
authors.affiliation: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458 schimmel@scripps.edu susan.ackerman@jax.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, ME 04609; schimmel@scripps.edu susan.ackerman@jax.org.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ackerman
mesh_terms: D000412:Alanine-tRNA Ligase / Q000172:deficiency* / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D004452:Echocardiography; D006331:Heart Diseases / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009154:Mutation; D032383:Myocytes, Cardiac / Q000648:ultrastructure; D010232:Paraffin / Q000737:chemistry; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D057165:Proteostasis Deficiencies / Q000235:genetics*; D017393:RNA Editing
chemical_list: D001426:Bacterial Proteins; D010232:Paraffin; D000412:Alanine-tRNA Ligase
keywords: cardiomyopathy; mistranslation; protein misfolding; protein quality control; translational fidelity