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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani
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Twin Attributes of Tyrosyl-tRNA Synthetase of Leishmania donovani

机译：利什曼原虫的酪氨酰-tRNA合成酶的双重属性

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摘要

Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes essential for protein synthesis. Apart from their parent aminoacylation activity, several aaRSs perform non-canonical functions in diverse biological processes. The present study explores the twin attributes of Leishmania tyrosyl-tRNA synthetase (LdTyrRS) namely, aminoacylation, and as a mimic of host CXC chemokine. Leishmania donovani is a protozoan parasite. Its genome encodes a single copy of tyrosyl-tRNA synthetase. We first tested the canonical aminoacylation role of LdTyrRS. The recombinant protein was expressed, and its kinetic parameters were determined by aminoacylation assay. To study the physiological role of LdTyrRS in Leishmania, gene deletion mutations were attempted via targeted gene replacement. The heterozygous mutants showed slower growth kinetics and exhibited attenuated virulence. LdTyrRS appears to be an essential gene as the chromosomal null mutants did not survive. Our data also highlights the non-canonical function of L. donovani tyrosyl-tRNA synthetase. We show that LdTyrRS protein is present in the cytoplasm and exits from the parasite cytoplasm into the extracellular medium. The released LdTyrRS functions as a neutrophil chemoattractant. We further show that LdTyrRS specifically binds to host macrophages with its ELR (Glu-Leu-Arg) peptide motif. The ELR-CXCR2 receptor interaction mediates this binding. This interaction triggers enhanced secretion of the proinflammatory cytokines TNF-α and IL-6 by host macrophages. Our data indicates a possible immunomodulating role of LdTyrRS in Leishmania infection. This study provides a platform to explore LdTyrRS as a potential target for drug development
机译：氨酰基-tRNA合成酶（aaRSs）是蛋白质合成必不可少的看家酶。除了它们的母体氨基酰化活性外，几种aaRS在各种生物学过程中还执行非典型功能。本研究探讨了利什曼原虫酪氨酰-tRNA合成酶（LdTyrRS）的双重属性，即氨酰化，并模拟了宿主CXC趋化因子。利什曼原虫是一种原生动物的寄生虫。它的基因组编码一个拷贝的酪氨酰-tRNA合成酶。我们首先测试了LdTyrRS的典型氨基酰化作用。表达重组蛋白，并通过氨基酰化法测定其动力学参数。为了研究LdTyrRS在利什曼原虫中的生理作用，尝试了通过靶向基因替代的基因缺失突变。杂合突变体显示较慢的生长动力学，并表现出弱毒力。 LdTyrRS似乎是必不可少的基因，因为染色体无效突变体无法存活。我们的数据还突出了杜氏乳酸酪氨酸-tRNA合成酶的非规范功能。我们显示LdTyrRS蛋白存在于细胞质中，并从寄生虫细胞质进入细胞外培养基。释放的LdTyrRS具有嗜中性粒细胞趋化作用。我们进一步表明，LdTyrRS特异性结合宿主巨噬细胞及其ELR（Glu-Leu-Arg）肽基序。 ELR-CXCR2受体相互作用介导了这种结合。这种相互作用触发宿主巨噬细胞分泌促炎细胞因子TNF-α和IL-6的分泌增加。我们的数据表明LdTyrRS在利什曼原虫感染中可能具有免疫调节作用。这项研究提供了一个平台，探讨LdTyrRS作为药物开发的潜在目标

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