Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR
Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR
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DOI：
10.1101/gad.17355911
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发表时间：
2011-10-01
影响因子：
10.5
通讯作者：
Lykke-Andersen, Jens
中科院分区：
文献类型：
--
作者：
Damgaard, Christian Kroun;Lykke-Andersen, Jens
细胞对环境变化的反应通常需要基因网络的协同调节，但人们对这如何在转录后水平发生知之甚少。转录后共调节的一个重要实例是响应于哺乳动物mRNA的生长条件的选择性翻译调节，所述哺乳动物mRNA编码蛋白质生物合成因子并含有标志性5 '末端寡嘧啶段（5' TOP）。然而，负责的反式因子和它们共同调节5 'TOP mRNA的机制仍然是难以捉摸的。在这里，我们确定了应激颗粒相关的TIA-1和TIAR蛋白作为人类5 'TOP mRNA调控的关键因子，其在氨基酸饥饿时组装到5' TOP mRNA的5'端并在起始步骤阻止翻译，如TIA-1/TIAR依赖性5' TOP mRNA翻译抑制、多核糖体释放和在应激颗粒中积累所证明的。这需要饥饿介导的GCN 2（一般控制非去阻遏2）激酶的激活和mTOR（雷帕霉素的哺乳动物靶蛋白）信号通路的失活。我们的研究结果为长期存在的问题提供了一个机制性解释，即5 'TOP mRNAs网络如何根据氨基酸的可用性进行协同调节，从而允许有限资源的重定向以启动营养剥夺反应。这提供了一个基本的例子，说明一组mRNA如何响应细胞环境的变化而进行协同调节。
The response of cells to changes in their environment often requires coregulation of gene networks, but little is known about how this can occur at the post-transcriptional level. An important example of post-transcriptional coregulation is the selective translational regulation in response to growth conditions of mammalian mRNAs that encode protein biosynthesis factors and contain hallmark 5'-terminal oligopyrimidine tracts (5'TOP). However, the responsible trans-factors and the mechanism by which they coregulate 5'TOP mRNAs have remained elusive. Here we identify stress granule-associated TIA-1 and TIAR proteins as key factors in human 5'TOP mRNA regulation, which upon amino acid starvation assemble onto the 5' end of 5'TOP mRNAs and arrest translation at the initiation step, as evidenced by TIA-1/TIAR-dependent 5'TOP mRNA translation repression, polysome release, and accumulation in stress granules. This requires starvation-mediated activation of the GCN2 (general control nonderepressible 2) kinase and inactivation of the mTOR (mammalian target of rapamycin) signaling pathway. Our findings provide a mechanistic explanation to the long-standing question of how the network of 5'TOP mRNAs are coregulated according to amino acid availability, thereby allowing redirection of limited resources to mount a nutrient deprivation response. This presents a fundamental example of how a group of mRNAs can be translationally coregulated in response to changes in the cellular environment.