Karasik Agnes, Lorenzi Hernan A, DePass Andrew V, Guydosh Nicholas R
Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
TriLab Bioinformatics Group, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
bioRxiv. 2023 Oct 1:2023.09.01.555507. doi: 10.1101/2023.09.01.555507.
Viral infection triggers several dsRNA sensors that lead to changes in gene expression in the cell. One of these sensors activates an endonuclease, RNase L, that cleaves single stranded RNA. However, how the resultant widespread RNA fragmentation affects gene expression is not fully understood. Here we show that this fragmentation induces the Ribotoxic Stress Response via ZAKα, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L limits the translation of stress-responsive genes, including antiviral mRNAs and that encodes an antagonist of the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage can evoke an antiviral program.
病毒感染会触发多种双链RNA传感器，从而导致细胞内基因表达发生变化。其中一种传感器会激活一种核酸内切酶RNase L，它能切割单链RNA。然而，由此产生的广泛RNA片段化如何影响基因表达尚未完全明确。在此我们表明，这种片段化通过ZAKα诱导核糖体毒性应激反应，可能是通过核糖体碰撞实现的。作为该反应一部分而被激活的p38和JNK信号通路会促进抑制病毒的结果，比如程序性细胞死亡。我们还表明，RNase L会限制应激反应基因的翻译，包括抗病毒mRNA以及编码整合应激反应拮抗剂的基因。有趣的是，我们发现通用核酸内切酶RNase A的活性概括了许多与激活的RNase L相同的分子表型，这表明广泛的RNA切割可引发抗病毒程序。
