期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：49
页码：17570-17575
DOI：10.1073/pnas.1420196111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMisfolded proteins are a hallmark of diverse human cardiac disorders including desmin-related cardiomyopathy and systemic amyloidosis. Defects in translational fidelity can cause neurodegeneration, however the consequences of mistranslation in other tissues, including the heart, are unknown. The fidelity of protein synthesis is largely ensured by aminoacyl-tRNA synthetases, and many tRNA synthetases contain editing domains that hydrolyze mischarged tRNAs, preventing incorporation of incorrect amino acids into proteins. Here, we show that diminished editing efficacy of the alanyl-tRNA synthetase causes misfolded protein aggregation and cell death in the mammalian heart. These results illuminate the importance of translational fidelity in cardiac homeostasis and suggest that genetic factors that disrupt the accuracy of translation may contribute to proteinopathies of the heart and other tissues. 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.
关键词：translational fidelity ; mistranslation ; protein misfolding ; protein quality control ; cardiomyopathy
