Heterotrimeric GAIT Complex Drives Transcript-Selective Translation Inhibition in Murine Macrophages
Heterotrimeric GAIT Complex Drives Transcript-Selective Translation Inhibition in Murine Macrophages
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DOI：
10.1128/mcb.01168-12
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发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Fox, Paul L.
中科院分区：
文献类型：
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作者：
Arif, Abul;Chatterjee, Piyali;Fox, Paul L.
人髓样细胞中γ干扰素（IFN -γ）激活的翻译抑制因子（GAIT）复合物是异源四聚体，由谷氨酰 - 脯氨酰 - tRNA合成酶（EPRS）、NS1相关蛋白1（NSAP1）、核糖体蛋白L13a和甘油醛 - 3 - 磷酸脱氢酶（GAPDH）组成。该复合物与血管内皮生长因子A（VEGF - A）及其他炎症相关转录本的3'非翻译区的结构GAIT元件结合，并抑制它们的翻译。EPRS首先在丝氨酸886位点被细胞周期蛋白依赖性激酶5（Cdk5）磷酸化，然后在丝氨酸999位点被一种依赖Cdk5的AGC激酶磷酸化；L13a在丝氨酸77位点被死亡相关蛋白激酶DAPK和ZIPK磷酸化。由于已知小鼠和人类的炎症反应存在显著差异，我们对小鼠巨噬细胞中的GAIT系统进行了研究。小鼠的GAIT复合物是异源三聚体，缺少NSAP1。与人类一样，IFN -γ通过诱导EPRS和L13a的磷酸化激活小鼠巨噬细胞GAIT系统。小鼠L13a在丝氨酸77位点被DAPK - ZIPK级联磷酸化，但EPRS仅在丝氨酸999位点被磷酸化。EPRS丝氨酸886位点磷酸化的缺失阻止NSAP1掺入GAIT复合物。然而，丝氨酸999位点磷酸化的EPRS、丝氨酸77位点磷酸化的L13a和GAPDH三者形成一个有功能的GAIT复合物，抑制GAIT靶mRNA的翻译。因此，小鼠中异源三聚体GAIT复合物的翻译调控体现了髓样细胞对炎症刺激的独特的物种特异性反应。
The gamma interferon (IFN-gamma)-activated inhibitor of translation (GAIT) complex in human myeloid cells is heterotetrameric, consisting of glutamyl-prolyl-tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The complex binds a structural GAIT element in the 3' untranslated region of VEGF-A and other inflammation-related transcripts and inhibits their translation. EPRS is dually phosphorylated by cyclin-dependent kinase 5 (Cdk5) at Ser(886) and then by a Cdk5-dependent-AGC kinase at Ser(999); L13a is phosphorylated at Ser(77) by death-associated protein kinases DAPK and ZIPK. Because profound differences in inflammatory responses between mice and humans are known, we investigated the GAIT system in mouse macrophages. The murine GAIT complex is heterotrimeric, lacking NSAP1. As in humans, IFN-gamma activates the mouse macrophage GAIT system via induced phosphorylation of EPRS and L13a. Murine L13a is phosphorylated at Ser(77) by the DAPK-ZIPK cascade, but EPRS is phosphorylated only at Ser(999). Loss of EPRS Ser(886) phosphorylation prevents NSAP1 incorporation into the GAIT complex. However, the triad of Ser(999)-phosphorylated EPRS, Ser(77)-phosphorylated L13a, and GAPDH forms a functional GAIT complex that inhibits translation of GAIT target mRNAs. Thus, translational control by the heterotrimeric GAIT complex in mice exemplifies the distinctive species-specific responses of myeloid cells to inflammatory stimuli.