An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response.
An RNA stem-loop functions in conjunction with an upstream open reading frame to direct preferential translation in the integrated stress response.
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DOI：
10.1016/j.jbc.2022.102864
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Wek, Ronald C.
中科院分区：
文献类型：
--
作者：
Amin, Parth H.;Carlson, Kenneth R.;Wek, Ronald C.
为了应对环境压力，细胞调用翻译控制来保存资源，并快速重新编程基因表达以实现最佳适应。翻译控制的中心机制涉及eIF 2 α亚基（p-eIF 2 α）的磷酸化，其减少起始tRNA向核糖体的递送。由于p-eIF 2 α被多种蛋白激酶激活，每种蛋白激酶对不同的应激反应，因此该途径被称为整合应激反应（ISR）。虽然p-eIF 2 α降低了整体翻译起始，但许多应激相关mRNA优先翻译。已知核糖体描绘基因转录物用于优先翻译的过程涉及嵌入靶mRNA中的上游开放阅读框（uORF）。在这项研究中，我们使用多核糖体分析和报告基因分析来解决指导ISR中人IBTKα优先翻译的机制。IBTKα mRNA编码4个uORFs，只有5′端的uORF 1和uORF 2被翻译。重要的是，IBTKα mRNA的5′-前导序列还含有一个中等稳定性的、在遗传学上保守的茎环，位于uORF 2下游11个核苷酸处。uORF 2翻译良好，与茎环结合发挥功能，有效降低IBTKα编码序列的翻译再起始。在应激诱导p-eIF 2 α后，uORF 2/茎环元件可以被绕过，以通过可能涉及适度翻译的uORF 1的机制来增强IBTKα翻译。我们的研究表明，uORF与RNA二级结构结合可以作为“条形码”的关键元素，通过扫描核糖体可以描绘哪些mRNA在ISR中优先翻译。
In response to environmental stresses, cells invoke translational control to conserve resources and rapidly reprogram gene expression for optimal adaptation. A central mechanism for translational control involves phosphorylation of the α subunit of eIF2 (p-eIF2α), which reduces delivery of initiator tRNA to ribosomes. Because p-eIF2α is invoked by multiple protein kinases, each responding to distinct stresses, this pathway is named the integrated stress response (ISR). While p-eIF2α lowers bulk translation initiation, many stress-related mRNAs are preferentially translated. The process by which ribosomes delineate gene transcripts for preferential translation is known to involve upstream open reading frames (uORFs) embedded in the targeted mRNAs. In this study, we used polysome analyses and reporter assays to address the mechanisms directing preferential translation of human IBTKα in the ISR. The IBTKα mRNA encodes four uORFs, with only 5′-proximal uORF1 and uORF2 being translated. Of importance, the 5′-leader of IBTKα mRNA also contains a phylogenetically conserved stem-loop of moderate stability that is situated 11 nucleotides downstream of uORF2. The uORF2 is well translated and functions in combination with the stem-loop to effectively lower translation reinitiation at the IBTKα coding sequence. Upon stress-induced p-eIF2α, the uORF2/stem loop element can be bypassed to enhance IBTKα translation by a mechanism that may involve the modestly translated uORF1. Our study demonstrates that uORFs in conjunction with RNA secondary structures can be critical elements that serve as the "bar code" by which scanning ribosomes can delineate which mRNAs are preferentially translated in the ISR.
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