RNase L mediates transient control of the interferon response through modulation of the double-stranded RNA-dependent protein kinase PKR
RNase L mediates transient control of the interferon response through modulation of the double-stranded RNA-dependent protein kinase PKR
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DOI：
10.1074/jbc.m208766200
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发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
Silverman, RH
中科院分区：
文献类型：
--
作者：
Khabar, KSA;Siddiqui, YM;Silverman, RH
针对不同形式的应激而发生的多种生物反应的瞬时控制通常是一个高度调控的过程。在干扰素 (IFN) 反应期间，双链 RNA 依赖性蛋白激酶 PKR 磷酸化真核起始因子 2α (eIF2α) 导致的翻译抑制构成了抑制病毒复制的一种手段。在这里，我们表明，针对急性病毒感染的 IFN 反应的短暂性至少部分是由 RNase L 调节的。在 RNase L 缺失细胞的 IFN 抗病毒反应过程中，PKR mRNA 稳定性增强，PKR 诱导增加，并且与类似处理的野生型细胞相比，eIF2α 的磷酸化形式出现了更长的动力学。通过监测病毒蛋白合成的抑制也证明了 RNase L 缺失细胞中 IFN 反应的增强。此外，质粒载体中 RNase L 的异位表达阻止了 PKR 的 IFN 诱导。这些结果表明 RNase L 在 IFN 反应以及可能的其他细胞因子和应激反应的瞬时控制中发挥作用。
The transient control of diverse biological responses that occurs in response to varied forms of stress is often a highly regulated process. During the interferon (IFN) response, translational repression due to phosphorylation of eukaryotic initiation factor 2alpha, eIF2alpha, by the double-stranded RNA-dependent protein kinase, PKR, constitutes a means of inhibiting viral replication. Here we show that the transient nature of the IFN response against acute viral infections is regulated, at least in part, by RNase L. During the IFN antiviral response in RNase L-null cells, PKR mRNA stability was enhanced, PKR induction was increased, and the phosphorylated form of eIF2alpha appeared with extended kinetics compared with similarly treated wild type cells. An enhanced IFN response in RNase L-null cells was also demonstrated by monitoring inhibition of viral protein synthesis. Furthermore, ectopic expression of RNase L from a plasmid vector prevented the IFN induction of PKR. These results suggest a role for RNase L in the transient control of the IFN response and possibly of other cytokine and stress responses.