Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment
Phosphorylation of Tristetraprolin by MK2 Impairs AU-Rich Element mRNA Decay by Preventing Deadenylase Recruitment
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DOI：
10.1128/mcb.00717-10
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发表时间：
2011-01-01
影响因子：
5.3
通讯作者：
Lykke-Andersen, Jens
中科院分区：
文献类型：
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作者：
Clement, Sandra L.;Scheckel, Claudia;Lykke-Andersen, Jens
信使核糖核酸的周转是控制基因表达的关键步骤。在哺乳动物细胞中，在mRNA周转水平调节的一组mRNAs在其3‘非翻译区含有不稳定的富含AU的元件(Ares)。这些转录本被一套ARE结合蛋白(AUBP)结合，AUBP从细胞信号事件中接收信息来调节ARE mRNA的衰退速度。在这里，我们发现了一个关键的不稳定的AUBP，Tristetraprolin(TTP)，由于磷酸化的TTP不能招募死烯基酶来靶向mRNAs，所以它被p38丝裂原活化蛋白激酶(MAPK)激活的激酶MK2抑制。TTP与胞质去烯基酶密切相关，在体外和细胞内促进靶mRNAs的快速去烯基化。当TTP被拴在异源mRNA上时，它可以指导底物mRNAs的去烯基化，但当被MK2磷酸化时，它的这一能力被抑制。磷酸化TTP在mRNA结合中没有受损，但不能招募主要的细胞质死烯基酶。这些观察表明，MK2对TTP的磷酸化主要通过防止死烯基化机制的重新启动来影响RNA结合下游的mRNA衰退。因此，一旦p38MAPK途径失活，TTP可能会迅速重新激活结合的转录本的去烯化，从而下调基因表达。
mRNA turnover is a critical step in the control of gene expression. In mammalian cells, a subset of mRNAs regulated at the level of mRNA turnover contain destabilizing AU-rich elements (AREs) in their 3' untranslated regions. These transcripts are bound by a suite of ARE-binding proteins (AUBPs) that receive information from cell signaling events to modulate rates of ARE mRNA decay. Here we show that a key destabilizing AUBP, tristetraprolin (TTP), is repressed by the p38 mitogen-activated protein kinase (MAPK)-activated kinase MK2 due to the inability of phospho-TTP to recruit deadenylases to target mRNAs. TTP is tightly associated with cytoplasmic deadenylases and promotes rapid deadenylation of target mRNAs both in vitro and in cells. TTP can direct the deadenylation of substrate mRNAs when tethered to a heterologous mRNA, yet its ability to do so is inhibited upon phosphorylation by MK2. Phospho-TTP is not impaired in mRNA binding but does fail to recruit the major cytoplasmic deadenylases. These observations suggest that phosphorylation of TTP by MK2 primarily affects mRNA decay downstream of RNA binding by preventing recruitment of the deadenylation machinery. Thus, TTP may remain poised to rapidly reactivate deadenylation of bound transcripts to downregulate gene expression once the p38 MAPK pathway is deactivated.