PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation
PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation
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PQBP1 通过抑制 eEF2 磷酸化促进翻译延伸并调节海马 mGluR-LTD
DOI：
10.1016/j.molcel.2021.01.032
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发表时间：
2021-04-01
期刊：
影响因子：
16
通讯作者：
Han, Junhai
中科院分区：
文献类型：
--
作者：
Shen, Yuqian;Zhang, Zi Chao;Han, Junhai
真核延伸因子2（eEF 2）介导肽基-tRNA从核糖体A位点移位到P位点以促进翻译延伸。其通过其单一已知激酶eEF 2K在Thr 56上的磷酸化使其失活并抑制翻译延伸。广泛的研究表明，不同的信号级联调节eEF 2K的活性，但是否有其他因素调节eEF 2的磷酸化仍不清楚，在这里，我们发现，X染色体连锁的智力残疾蛋白聚谷氨酰胺结合蛋白1（PQBP 1）特异性结合非磷酸化的eEF 2和抑制eEF 2K介导的磷酸化在Thr 56。PQBP 1的缺失通过抑制翻译延伸而显著降低一般蛋白质合成。此外，我们发现PQBP 1通过抑制eEF 2K介导的磷酸化来调节海马代谢型谷氨酸受体依赖性长期抑郁（mGluR-LTD）和mGluR-LTD相关行为。我们的研究结果将PQBP 1确定为翻译延伸和mGluR-LTD中的新型调节剂，并且这种新发现的eEF 2K/eEF 2途径中的调节剂也是各种疾病的极好治疗靶点，例如神经疾病，病毒感染和癌症。
Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear, Here, we find that the X chromosome-linked intellectual disability protein polyglutaminebinding protein 1 (PQBP1) specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56. Loss of PQBP1 significantly reduces general protein synthesis by suppressing translational elongation. Moreover, we show that PQBP1 regulates hippocampal metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and mGluR-LTD-associated behaviors by suppressing eEF2K-mediated phosphorylation. Our results identify PQBP1 as a novel regulator in translational elongation and mGluR-LTD, and this newly revealed regulator in the eEF2K/eEF2 pathway is also an excellent therapeutic target for various disease conditions, such as neural diseases, virus infection, and cancer.