Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements.
Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements.
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DOI：
10.1261/rna.054833.115
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Lykke-Andersen J
中科院分区：
文献类型：
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作者：
Fu R;Olsen MT;Webb K;Bennett EJ;Lykke-Andersen J
锌指蛋白三戊三脯氨酸（TTP）促进含有富au元素（AREs）的mrna的翻译抑制和降解。尽管人们对TTP的衰变过程和机制有了更多的了解，但TTP的翻译抑制作用仍然知之甚少。在这里，我们发现帽结合翻译抑制4EHP-GYF2复合体是TTP的辅助因子。免疫沉淀和体外拉下实验表明，TTP通过与GYF2的直接相互作用与4EHP-GYF2复合物结合，突变分析表明，这种相互作用是通过TTP的保守四脯氨酸基序发生的。4EHP-GYF2结合减少的TTP突变体抑制荧光素酶报告基因ARE-mRNA的能力受损。与野生型mef相比，ehp敲除小鼠胚胎成纤维细胞（mef）显示ttp靶mrna的诱导增加和较慢的周转。我们的工作强调了TTP保守的四脯氨酸基序的功能，并确定了4EHP-GYF2是TTP翻译抑制和mRNA衰变的辅助因子。
The zinc finger protein tristetraprolin (TTP) promotes translation repression and degradation of mRNAs containing AU-rich elements (AREs). Although much attention has been directed toward understanding the decay process and machinery involved, the translation repression role of TTP has remained poorly understood. Here we identify the cap-binding translation repression 4EHP-GYF2 complex as a cofactor of TTP. Immunoprecipitation and in vitro pull-down assays demonstrate that TTP associates with the 4EHP-GYF2 complex via direct interaction with GYF2, and mutational analyses show that this interaction occurs via conserved tetraproline motifs of TTP. Mutant TTP with diminished 4EHP-GYF2 binding is impaired in its ability to repress a luciferase reporter ARE-mRNA. 4EHP knockout mouse embryonic fibroblasts (MEFs) display increased induction and slower turnover of TTP-target mRNAs as compared to wild-type MEFs. Our work highlights the function of the conserved tetraproline motifs of TTP and identifies 4EHP-GYF2 as a cofactor in translational repression and mRNA decay by TTP.