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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript- selective translational control
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Phosphorylation of glutamyl-prolyl tRNA synthetase by cyclin-dependent kinase 5 dictates transcript- selective translational control

机译：细胞周期蛋白依赖性激酶5对谷氨酰脯氨酰tRNA合成酶的磷酸化决定了转录本选择性翻译控制

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摘要

Cyclin-dependent kinase 5 (Cdk5) is an atypical but essential member of the Cdk kinase family, and its dysregulation or deletion has been implicated in inflammation-related disorders by an undefined mechanism. Here we show that Cdk5 is an indispensable activator of the GAIT (IFN-γ-activated inhibitor of translation) pathway, which suppresses expression of a posttranscriptional regulon of proinflammatory genes in myeloid cells. Through induction of its regulatory protein, Cdk5R1 (p35), IFN-γ activates Cdk5 to phosphorylate Ser~(886) in the linker domain of glutamyl-prolyl tRNA synthetase (EPRS), the initial event in assembly of the GAIT complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of Ser~(999), the second essential event in GAIT pathway activation. Diphosphorylated EPRS is released from its residence in the tRNA multisynthetase complex for immediate binding to NS1-associated protein and subsequent binding to ribosomal protein L13a and GAPDH. The mature heterotetra-meric GAIT complex binds the 3' UTR GAIT element of VEGF-A and other target mRNAs and suppresses their translation in myeloid cells. Inhibition of Cdk5/p35 inhibits both EPRS phosphorylation events, prevents EPRS release from the tRNA multisynthetase complex, and blocks translational suppression of GAIT element-bearing mRNAs, resulting in increased expression of inflammatory proteins. Our study reveals a unique role of Cdk5/p35 in activation of the major noncanonical function of EPRS, namely translational control of macrophage inflammatory gene expression.
机译：细胞周期蛋白依赖性激酶5（Cdk5）是Cdk激酶家族的一个非典型但必不可少的成员，其失调或缺失已通过不确定的机制与炎症相关的疾病有关。在这里，我们显示Cdk5是GAIT（IFN-γ激活的翻译抑制剂）途径的必不可少的激活剂，它抑制了髓样细胞中促炎基因转录后调控的表达。通过诱导其调节蛋白Cdk5R1（p35），IFN-γ激活Cdk5以使谷氨酰脯氨酰tRNA合成酶（EPRS）的连接域中的Ser〜（886）磷酸化，这是GAIT复合体装配的初始事件。 Cdk5 / p35尽管通过独特的激酶间接诱导，但也诱导了Ser〜（999）的磷酸化，这是GAIT途径激活中的第二个基本事件。二磷酸化的EPRS从其在tRNA多合成酶复合物中的驻留中释放出来，可立即与NS1相关蛋白结合，随后与核糖体蛋白L13a和GAPDH结合。成熟的异四聚体GAIT复合物结合VEGF-A和其他靶标mRNA的3'UTR GAIT元件，并抑制它们在髓样细胞中的翻译。抑制Cdk5 / p35可同时抑制EPRS磷酸化事件，防止EPRS从tRNA多合成酶复合物中释放，并阻止GAIT元件mRNA的翻译抑制，从而导致炎症蛋白表达增加。我们的研究揭示了Cdk5 / p35在激活EPRS的主要非经典功能（即巨噬细胞炎症基因表达的翻译控制）中的独特作用。

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    Abul Arif; Jie Jia; Robyn A. Moodt; Paul E. DiCorleto; Paul L. Fox;

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    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

    Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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