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首页> 外文期刊>Cell Research >Interferon-γ mRNA attenuates its own translation by activating PKR: A molecular basis for the therapeutic effect of interferon-β in multiple sclerosis
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Interferon-γ mRNA attenuates its own translation by activating PKR: A molecular basis for the therapeutic effect of interferon-β in multiple sclerosis

机译：干扰素-γmRNA通过激活PKR减弱其自身翻译：干扰素-β在多发性硬化症中治疗作用的分子基础

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摘要

PKR, the interferon (IFN)-inducible protein kinase activated by double-stranded RNA, inhibits translation by phos-phorylating the initiation factor eIF2α chain. Uniquely, human IFN-γ mRNA uses local activation of PKR in the cell to control its own-translation yield. IFN-γ mRNA activates PKR through a structure in its 5'- region harboring a pseudoknot which is critical for PKR activation. Mutations that impair pseudoknot stability reduce the ability of IFN-γ mRNA to activate PKR and strongly increase its translation efficiency. The cis-acting RNA element in IFN-γ mRNA functions as a biological sensor of intracellular PKR levels. During an immune response, as IFN-γ and other inflammatory cyto-kines build up in the cell's microenvironment, they act to induce higher levels of PKR in the cell, resulting in a more extensive activation of PKR by IFN-γ mRNA. With the resulting phosphorylation of eIF2α, a negative feedback loop is created and the production of IFN-γ is progressively attenuated. We propose that the therapeutic effect of IFN-β in multiple sclerosis may rest, at least in part, on its exquisite ability to induce high levels of PKR in the cell and thereby to limit IFN-γ mRNA translation through this negative feedback loop, blocking the excessive IFN-γ gene expression that precedes clinical attacks.
机译：PKR是被双链RNA激活的干扰素（IFN）诱导蛋白激酶，可通过磷酸化起始因子eIF2α链来抑制翻译。独特的是，人IFN-γmRNA利用细胞中PKR的局部活化来控制自身的翻译产量。 IFN-γmRNA通过其5'-区域中的结构激活PKR，该结构具有对PKR激活至关重要的假结。削弱假结稳定性的突变会降低IFN-γmRNA激活PKR的能力，并大大提高其翻译效率。 IFN-γmRNA中的顺式作用RNA元件可作为细胞内PKR水平的生物传感器。在免疫反应过程中，随着IFN-γ和其他炎性细胞因子在细胞微环境中的积累，它们的作用是诱导细胞中更高水平的PKR，从而导致IFN-γmRNA对PKR的活化更为广泛。随着eIF2α的磷酸化，产生了一个负反馈回路，并且IFN-γ的产生逐渐减弱。我们建议，IFN-β在多发性硬化症中的治疗作用可能至少部分取决于其诱导细胞中高水平PKR的精湛能力，从而通过这种负反馈回路限制IFN-γmRNA的翻译，从而阻断临床发作之前过度的IFN-γ基因表达。

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