Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation.
Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation.
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DOI：
10.1101/gad.231407.113
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发表时间：
2014-02-15
影响因子：
10.5
通讯作者：
Roux PP
中科院分区：
文献类型：
--
作者：
Tcherkezian J;Cargnello M;Romeo Y;Huttlin EL;Lavoie G;Gygi SP;Roux PP
哺乳动物靶标雷帕霉素(MTOR)可促进信使核糖核酸的翻译、细胞生长和增殖。在定量蛋白质组筛查中，TCherkezian等人。以mTOR依赖的方式鉴定与mRNA5‘帽相关的蛋白质。作者发现，假定的RNA结合蛋白LARP1刺激含有5‘末端寡嘧啶(TOP)基序的mRNAs的翻译。LARP1与mTOR复合体1结合，是全球蛋白质合成所必需的。这些数据揭示了5‘TOP mRNA翻译的新机制，并暗示LARP1是一个关键的细胞生长调节因子。哺乳动物靶标雷帕霉素(MTOR)通过促进mRNA的翻译和增加细胞的蛋白质合成能力来促进细胞的生长和增殖。虽然mTOR通过调节mRNA5‘端帽子结合蛋白eIF4E(真核细胞起始因子4E)来促进翻译，但它也通过不清楚的机制优先调节某些类别的mRNA的翻译。为了帮助填补这一知识空白，我们进行了一项定量蛋白质组筛选，以确定以mTOR依赖的方式与mRNA5‘帽相关的蛋白质。使用这一方法，我们确定了许多潜在的调节因子，包括假定的RNA结合蛋白LARP1(La相关蛋白1)。我们的结果表明，LARP1通过PABP与主动翻译核糖体有关，LARP1刺激含有5‘末端寡嘧啶(TOP)基序的mRNAs的翻译，该基序编码翻译机制的组成部分。我们发现LARP1与mTOR复合体1(MTORC1)有关，是全球蛋白质合成以及细胞生长和增殖所必需的。综上所述，这些数据揭示了参与TOP mRNA翻译的重要分子机制，并暗示LARP1是细胞生长和增殖的重要调节因子。
The mammalian target of rapamycin (mTOR) promotes mRNA translation, cell growth, and proliferation. In a quantitative proteomic screen, Tcherkezian et al. identify proteins that associate with the mRNA 5′ cap in an mTOR-dependent manner. The authors show that the putative RNA-binding protein LARP1 stimulates the translation of mRNAs containing a 5′ terminal oligopyrimidine (TOP) motif. LARP1 associates with the mTOR complex 1 and is required for global protein synthesis. The data reveal new mechanisms of 5′TOP mRNA translation and implicate LARP1 as a key cell growth regulator. The mammalian target of rapamycin (mTOR) promotes cell growth and proliferation by promoting mRNA translation and increasing the protein synthetic capacity of the cell. Although mTOR globally promotes translation by regulating the mRNA 5′ cap-binding protein eIF4E (eukaryotic initiation factor 4E), it also preferentially regulates the translation of certain classes of mRNA via unclear mechanisms. To help fill this gap in knowledge, we performed a quantitative proteomic screen to identify proteins that associate with the mRNA 5′ cap in an mTOR-dependent manner. Using this approach, we identified many potential regulatory factors, including the putative RNA-binding protein LARP1 (La-related protein 1). Our results indicate that LARP1 associates with actively translating ribosomes via PABP and that LARP1 stimulates the translation of mRNAs containing a 5′ terminal oligopyrimidine (TOP) motif, encoding for components of the translational machinery. We found that LARP1 associates with the mTOR complex 1 (mTORC1) and is required for global protein synthesis as well as cell growth and proliferation. Together, these data reveal important molecular mechanisms involved in TOP mRNA translation and implicate LARP1 as an important regulator of cell growth and proliferation.
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