Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy
Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy
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DOI：
10.1073/pnas.1420196111
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发表时间：
2014-12-09
影响因子：
11.1
通讯作者：
Ackerman, Susan L.
中科院分区：
文献类型：
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作者：
Liu, Ye;Satz, Jakob S.;Ackerman, Susan L.
错误折叠的蛋白质是心脏病的新标志。虽然一些错误折叠的蛋白质，如去蛋白蛋白，与编码这些疾病相关蛋白的基因突变有关，但对于心脏中产生错误折叠蛋白的更一般机制知之甚少。alanyl-tRNA合成酶（AlaRS）编辑域的亚形态突变导致翻译保真度降低，导致特定小鼠神经元中错误折叠蛋白的积累。通过对AlaRS编辑活性的进一步遗传调节，我们生成了具有更广泛表型的小鼠模型，其严重程度与编辑受损的程度直接相关。AlaRS编辑活性的严重破坏会导致胚胎致死，而AlaRS编辑效果的中度降低会导致心肌细胞泛素化蛋白聚集和线粒体缺陷，并伴有进行性心脏纤维化和功能障碍。此外，自噬空泡在突变心肌细胞中积累，表明自噬不足以消除错误折叠的蛋白质。这些发现表明，tRNA合成酶编辑活性降低的病理后果，以及翻译不忠，取决于细胞类型和编辑中断的程度，并提供了一种以前未被发现的心脏蛋白病的机制。
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.