Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
Cell-Type-Specific Effects of RNase L on Viral Induction of Beta Interferon
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DOI：
10.1128/mbio.00856-14
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发表时间：
2014-03-01
期刊：
影响因子：
6.4
通讯作者：
Silverman, Robert H.
中科院分区：
文献类型：
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作者：
Banerjee, Shuvojit;Chakrabarti, Arindam;Silverman, Robert H.
干扰素（IFN）诱导的抗病毒状态部分由2 '，5 '-寡腺苷酸（2-5A）合成酶（OAS）/ RNase L系统介导。2-5A，由OAS蛋白响应病毒双链RNA从ATP产生，结合并激活RNase L。RNA酶L通过降解病毒和细胞RNA、诱导自噬和凋亡以及产生RNA降解产物来限制病毒感染，所述RNA降解产物通过RIG-I样受体放大I型干扰素（IFN）的产生。然而，OAS/RNase L途径对这些蛋白质的基础水平不同的不同细胞类型中的IFN诱导的影响以前尚未报道。在这里，我们报告了小鼠巨噬细胞中RNase L和OAS的基础表达高于小鼠胚胎成纤维细胞（MEFs）。在MEFs中，RNase L基因敲除降低了脑心肌炎病毒感染或poly（rI）：poly（rC）（pIC）转染对IFN-β的诱导。相反，在巨噬细胞中，RNA酶L缺失增加（而不是减少）病毒或pIC对IFN-β的诱导。在病毒感染的巨噬细胞中，RNA酶L造成的RNA损伤可能是导致IFN-β产生减少的原因。类似地，通过用2-5A转染直接激活RNase L在MEF中诱导IFN-β，但在巨噬细胞中不诱导。此外，病毒感染或pIC转染引起RNase L依赖的巨噬细胞凋亡，但不是MEFs。我们的研究结果表明，OAS和RNase L的基础水平的细胞类型特异性差异是IFN-β诱导的决定因素，可能会影响组织保护和生存在病毒infections.IMPORTANCE I型干扰素（IFN-β），如IFN-β是必不可少的抗病毒细胞因子，通常需要为动物生存感染后的高致病性病毒。因此，调节I型IFN产生的宿主因子对动物和人类健康至关重要。以前我们报道过OAS/RNase L通路通过增强小鼠胚胎成纤维细胞和病毒感染小鼠中IFN-β的产生来增强抗病毒先天免疫。在这里，我们报告说，高基础水平的OAS/RNase L在巨噬细胞减少，而不是增加，病毒诱导IFN-β。RNase L引起的RNA损伤和细胞凋亡可能是病毒感染的巨噬细胞产生IFN-β减少的原因。我们的研究表明，在病毒感染期间，OAS/RNase L途径可以增强或抑制IFN的产生，这取决于细胞类型。RNA酶L对IFN的调节被认为有助于病毒感染期间的组织保护和存活。
The interferon (IFN)-inducible antiviral state is mediated in part by the 2 ', 5 '-oligoadenylate (2-5A) synthetase (OAS)/ RNase L system. 2-5A, produced from ATP by OAS proteins in response to viral double-stranded RNA, binds to and activates RNase L. RNase L restricts viral infections by degrading viral and cellular RNA, inducing autophagy and apoptosis, and producing RNA degradation products that amplify production of type I interferons (IFNs) through RIG-I-like receptors. However, the effects of the OAS/RNase L pathway on IFN induction in different cell types that vary in basal levels of these proteins have not been previously reported. Here we report higher basal expression of both RNase L and OAS in mouse macrophages in comparison to mouse embryonic fibroblasts (MEFs). In MEFs, RNase L gene knockout decreased induction of IFN-beta by encephalomyocarditis virus infection or poly(rI): poly(rC) (pIC) transfection. In contrast, in macrophages, RNase L deletion increased (rather than decreased) induction of IFN-beta by virus or pIC. RNA damage from RNase L in virus-infected macrophages is likely responsible for reducing IFN-beta production. Similarly, direct activation of RNase L by transfection with 2-5A induced IFN-beta in MEFs but not in macrophages. Also, viral infection or pIC transfection caused RNase L-dependent apoptosis of macrophages but not of MEFs. Our results suggest that cell-type-specific differences in basal levels of OAS and RNase L are determinants of IFN-beta induction that could affect tissue protection and survival during viral infections.IMPORTANCE Type I interferons (IFNs) such as IFN-beta are essential antiviral cytokines that are often required for animal survival following infections by highly pathogenic viruses. Therefore, host factors that regulate type I IFN production are critically important for animal and human health. Previously we reported that the OAS/RNase L pathway amplifies antiviral innate immunity by enhancing IFN-beta production in mouse embryonic fibroblasts and in virus-infected mice. Here we report that high basal levels of OAS/RNase L in macrophages reduce, rather than increase, virus induction of IFN-beta. RNA damage and apoptosis caused by RNase L were the likely reasons for the decreased IFN-beta production in virus-infected macrophages. Our studies suggest that during viral infections, the OAS/RNase L pathway can either enhance or suppress IFN production, depending on the cell type. IFN regulation by RNase L is suggested to contribute to tissue protection and survival during viral infections.