mRNA structure regulates protein expression through changes in functional half-life
mRNA structure regulates protein expression through changes in functional half-life
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DOI：
10.1073/pnas.1908052116
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发表时间：
2019-11-26
影响因子：
11.1
通讯作者：
McFadyen, Iain J.
中科院分区：
文献类型：
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作者：
Mauger, David M.;Cabral, B. Joseph;McFadyen, Iain J.
信使rna (mrna)在其初级序列和高阶结构中编码信息。密码子使用和二级结构等因素对调节蛋白质表达的独立贡献难以确定，因为它们通常在内源序列中高度相关。在这里，我们使用了两种方法，修饰核苷酸的全局包含和外源性递送构建体的合理序列设计，来了解mRNA二级结构独立于密码子使用的作用。出乎意料的是，高表达mrna包含一个高度结构化的编码序列（CDS）。稳定mRNA二级结构的修饰核苷酸使其能够在各种初级序列中实现高表达。使用一组密码子使用和CDS结构独立改变的eGFP mRNA，我们发现CDS的结构通过改变mRNA的功能半衰期（即mRNA被主动翻译）来调节蛋白质表达。这项工作强调了mRNA二级结构在mRNA稳定性调节中的作用。
Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used 2 approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs, to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly expressed mRNAs contained a highly structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide variety of primary sequences. Using a set of eGFP mRNAs with independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e., mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability.