Global Analysis of mRNA, Translation, and Protein Localization: Local Translation Is a Key Regulator of Cell Protrusions
Global Analysis of mRNA, Translation, and Protein Localization: Local Translation Is a Key Regulator of Cell Protrusions
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DOI：
10.1016/j.devcel.2015.10.005
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发表时间：
2015-11-09
影响因子：
11.8
通讯作者：
Marshall, Christopher J.
中科院分区：
文献类型：
--
作者：
Mardakheh, Faraz K.;Paul, Angela;Marshall, Christopher J.
细胞极化为突出的前沿和收缩的细胞体是间充质样细胞迁移的标志。许多信使核糖核酸（mRNAs）定位于突起部位，但尚不清楚mRNA定位在多大程度上有助于突起的形成。我们通过RNA测序（RNA - seq）和定量蛋白质组学对突起部位和细胞体之间的mRNAs、蛋白质分布以及翻译速率进行了全面的定量分析。我们的结果表明，局部翻译是蛋白质定位于突起部位的关键决定因素。因此，抑制局部翻译会使突起不稳定并抑制间充质样形态。有趣的是，许多定位于突起部位的mRNAs在翻译上受到抑制。mRNA非翻译区（UTRs）内特定的顺式调控元件决定了mRNAs是在局部进行翻译还是受到抑制。最后，对富集在突起部位的RNA结合蛋白（RBPs）进行RNA干扰筛选，揭示了局部翻译的反式调节因子，这些因子对突起具有重要的功能。我们提出，通过解读局部mRNA非翻译区密码，这些蛋白质可调节突起的稳定性和间充质样形态。
Polarization of cells into a protrusive front and a retracting cell body is the hallmark of mesenchymal-like cell migration. Many mRNAs are localized to protrusions, but it is unclear to what degree mRNA localization contributes toward protrusion formation. We performed global quantitative analysis of the distributions of mRNAs, proteins, and translation rates between protrusions and the cell body by RNA sequencing (RNA-seq) and quantitative proteomics. Our results reveal local translation as a key determinant of protein localization to protrusions. Accordingly, inhibition of local translation destabilizes protrusions and inhibits mesenchymal-like morphology. Interestingly, many mRNAs localized to protrusions are translationally repressed. Specific cis-regulatory elements within mRNA UTRs define whether mRNAs are locally translated or repressed. Finally, RNAi screening of RNA-binding proteins (RBPs) enriched in protrusions revealed trans-regulators of localized translation that are functionally important for protrusions. We propose that by deciphering the localized mRNA UTR code, these proteins regulate protrusion stability and mesenchymal-like morphology.