Burke James M, Moon Stephanie L, Matheny Tyler, Parker Roy
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA; Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309, USA.
Mol Cell. 2019 Sep 19;75(6):1203-1217.e5. doi: 10.1016/j.molcel.2019.07.029. Epub 2019 Sep 4.
In response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2α phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by allowing translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such as interferon (IFN)-β. Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNase L reprograms translation in response to dsRNA.
作为对外源和内源性双链RNA（dsRNA）的反应，蛋白激酶R（PKR）和核糖核酸酶L（RNase L）会对哺乳动物细胞中的翻译进行重新编程。PKR通过真核翻译起始因子2α（eIF2α）磷酸化来抑制翻译起始，这会触发应激颗粒（SG）的形成并促进应激反应性mRNA的翻译。RNase L驱动的翻译抑制机制、其对应激颗粒组装的贡献以及对dsRNA应激诱导的mRNA的调控尚不清楚。我们证明，RNase L通过促进mRNA的广泛周转来驱动对dsRNA的翻译关闭。这改变了应激颗粒的组装，并通过允许对RNase L降解具有抗性的mRNA（包括许多抗病毒mRNA，如干扰素（IFN）-β）进行翻译来重新编程翻译。单个细胞以不同方式激活dsRNA反应，揭示了可能影响细胞结果的差异。这确定了大量mRNA降解和抗病毒mRNA的抗性是RNase L响应dsRNA重新编程翻译的机制。
