Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642, USA.
Undergraduate Program in Biology and Medicine, Department of Biological Sciences: Biochemistry, University of Rochester, Rochester, NY 14620, USA.
Cells. 2023 Dec 22;13(1):35. doi: 10.3390/cells13010035.
Glutamyl-prolyl-tRNA synthetase (EPRS1), an aminoacyl-tRNA synthetase (ARS) ligating glutamic acid and proline to their corresponding tRNAs, plays an essential role in decoding proline codons during translation elongation. The physiological function of EPRS1 in cardiomyocytes (CMs) and the potential effects of the CM-specific loss of Eprs1 remain unknown. Here, we found that heterozygous Eprs1 knockout in CMs does not cause any significant changes in CM hypertrophy induced by pressure overload, while homozygous knockout leads to dilated cardiomyopathy, heart failure, and lethality at around 1 month after Eprs1 deletion. The transcriptomic profiling of early-stage Eprs1 knockout hearts suggests a significantly decreased expression of multiple ion channel genes and an increased gene expression in proapoptotic pathways and integrated stress response. Proteomic analysis shows decreased protein expression in multi-aminoacyl-tRNA synthetase complex components, fatty acids, and branched-chain amino acid metabolic enzymes, as well as a compensatory increase in cytosolic translation machine-related proteins. Immunoblot analysis indicates that multiple proline-rich proteins were reduced at the early stage, which might contribute to the cardiac dysfunction of Eprs1 knockout mice. Taken together, this study demonstrates the physiological and molecular outcomes of loss-of-function of Eprs1 in vivo and provides valuable insights into the potential side effects on CMs, resulting from the EPRS1-targeting therapeutic approach.
谷氨酰-脯氨酰-tRNA 合成酶（EPRS1）是一种氨酰-tRNA 合成酶（ARS），可将谷氨酸和脯氨酸连接到其相应的 tRNA 上，在翻译延伸过程中对解码脯氨酸密码子起着至关重要的作用。EPRS1 在心肌细胞（CMs）中的生理功能以及 CM 特异性缺失 Eprs1 的潜在影响尚不清楚。在这里，我们发现 CMs 中的杂合 Eprs1 敲除不会导致压力超负荷诱导的 CM 肥大发生任何显著变化，而纯合敲除会导致扩张型心肌病、心力衰竭，并在 Eprs1 删除后约 1 个月内导致死亡。早期 Eprs1 敲除心脏的转录组谱分析表明，多个离子通道基因的表达显著降低，促凋亡途径和整合应激反应的基因表达增加。蛋白质组分析显示多氨酰-tRNA 合成酶复合物成分、脂肪酸和支链氨基酸代谢酶的蛋白表达减少，同时细胞溶质翻译机器相关蛋白的代偿性增加。免疫印迹分析表明，早期有多种富含脯氨酸的蛋白减少，这可能导致 Eprs1 敲除小鼠的心脏功能障碍。总之，本研究证明了 Eprs1 在体内失活的生理和分子结果，并为 EPRS1 靶向治疗方法对 CMs 可能产生的潜在副作用提供了有价值的见解。
