La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region
La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region
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DOI：
10.1093/nar/gkx1237
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发表时间：
2018-02-16
影响因子：
14.9
通讯作者：
Thoreen, Carson C.
中科院分区：
文献类型：
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作者：
Philippe, Lucas;Vasseur, Jean-Jacques;Thoreen, Carson C.
细胞生长是一个复杂的过程，由基因表达的广泛和协调变化塑造。其中之一是由5‘末端寡嘧啶(TOP)基序定义的生长相关mRNAs家族的严格调控翻译。TOP mRNA的翻译部分受真核细胞起始因子4F(EIF4F)的控制，eIF4F是一种识别mRNA5‘帽结构的翻译因子。最近的研究还涉及La相关蛋白1(LARP1)，它与eIF4F竞争结合mRNA5‘端。然而，LARP1是否直接抑制顶端信使核糖核酸的翻译，以及如果是的话，其信使核糖核酸靶标的特征仍然存在争议。在这里，我们证明了LARP1的C-末端半部分对于控制细胞中TOP mRNA的翻译是必要的和充分的。该片段包含我们确定的DM15帽结合结构域以及邻近的调节区。我们进一步证明，纯化的LARP1通过联合识别顶端序列和帽子结构来抑制TOP mRNA的体外翻译，并且其内在的抑制活性和对这些特征的亲和力受到调节。这些结果支持一种模型，即顶级mRNAs的翻译由eIF4F和LARP1之间对其5‘端的生长调控竞争控制。
Cell growth is a complex process shaped by extensive and coordinated changes in gene expression. Among these is the tightly regulated translation of a family of growth-related mRNAs defined by a 5' terminal oligopyrimidine (TOP) motif. TOP mRNA translation is partly controlled via the eukaryotic initiation factor 4F (eIF4F), a translation factor that recognizes the mRNA 5' cap structure. Recent studies have also implicated La-related protein 1 (LARP1), which competes with eIF4F for binding to mRNA 5' ends. However, it has remained controversial whether LARP1 represses TOP mRNA translation directly and, if so, what features define its mRNA targets. Here, we show that the C-terminal half of LARP1 is necessary and sufficient to control TOP mRNA translation in cells. This fragment contains the DM15 capbinding domain as well as an adjacent regulatory region that we identified. We further demonstrate that purified LARP1 represses TOP mRNA translation in vitro through the combined recognition of both the TOP sequence and cap structure, and that its intrinsic repressive activity and affinity for these features are subject to regulation. These results support a model whereby the translation of TOP mRNAs is controlled by a growth-regulated competition between eIF4F and LARP1 for their 5' ends.