EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice.
EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice.
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DOI：
10.1038/nature21380
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发表时间：
2017-02-16
期刊：
影响因子：
64.8
通讯作者：
Fox PL
中科院分区：
文献类型：
--
作者：
Arif A;Terenzi F;Potdar AA;Jia J;Sacks J;China A;Halawani D;Vasu K;Li X;Brown JM;Chen J;Kozma SC;Thomas G;Fox PL
导致肥胖和衰老的代谢途径由雷帕霉素复合物1（mTORC 1）和p70核糖体蛋白S6激酶1（S6 K1）轴的哺乳动物靶激活。然而，已知的mTORC 1-S6 K1靶标不能解释观察到的功能丧失表型，这表明存在其他下游效应物。在这里，我们确定谷氨酰-脯氨酰tRNA合成酶（EPRS）作为mTORC 1-S6 K1的目标，有助于肥胖和衰老的重要。mTORC 1-S6 K1在Ser 999处的EPRS磷酸化诱导其从氨酰tRNA多合成酶复合物（MSC）中释放，这是执行蛋白质合成以外的非经典功能所需的。为了研究EPRS磷酸化的生理功能，我们产生了携带磷酸缺陷Ser 999-to-Ala（S999 A）和磷酸模拟（S999 D）突变的EPRS基因敲入小鼠。纯合子S999 A小鼠表现出低体重、脂肪组织质量减少和寿命延长，从而与S6 K1缺陷小鼠和脂肪细胞特异性raptor缺陷小鼠（mTORC 1组分）表现出显著的相似性。在S6 K1缺陷小鼠中，EPRS S999 D等位基因的取代使体重和肥胖正常化，表明EPRS磷酸化介导S6 K1依赖性代谢反应。在脂肪细胞中，胰岛素刺激S6 K1依赖性EPRS磷酸化和从MSC释放。相互作用筛选显示磷酸-EPRS结合Slc 27 a1（即，脂肪酸转运蛋白1，FATP 1），诱导其转运到质膜和长链脂肪酸摄取。因此，EPRS和FATP 1是代谢表型的关键末端mTORC 1-S6 K1轴效应子。
Metabolic pathways contributing to adiposity and aging are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting additional downstream effectors. Here we identify glutamyl-prolyl tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes importantly to adiposity and aging. EPRS phosphorylation at Ser999 by mTORC1-S6K1 induces its release from the aminoacyl tRNA multisynthetase complex (MSC), required for execution of noncanonical functions beyond protein synthesis. To investigate physiological function of EPRS phosphorylation, we generated EPRS knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, thereby displaying notable similarities with S6K1-deficient mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the EPRS S999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the MSC. Interaction screening revealed phospho-EPRS binds Slc27a1 (i.e., fatty acid transport protein 1, FATP1), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1-S6K1 axis effectors critical for metabolic phenotypes.