Reovirus σ3 Protein Limits Interferon Expression and Cell Death Induction.
Reovirus σ3 Protein Limits Interferon Expression and Cell Death Induction.
复制标题
呼肠孤病毒Ï3 蛋白限制干扰素表达和细胞死亡诱导。
DOI：
10.1128/jvi.01485-20
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发表时间：
2020
影响因子：
5.4
通讯作者：
Danthi,Pranav
中科院分区：
文献类型：
--
作者：
Roebke,KatherineE;Guo,Yingying;Parker,JohnSL;Danthi,Pranav
哺乳动物呼肠孤病毒诱导坏死性凋亡需要 I 型干扰素 (IFN) 信号传导和病毒复制事件，从而产生子代基因组双链 RNA (dsRNA)。呼肠孤病毒外衣壳蛋白 μ1 通过限制 RNA 合成来负调节呼肠孤病毒诱导的坏死性凋亡。为了确定与 μ1 相互作用的外衣壳蛋白 σ3 是否也具有调节坏死性凋亡的功能，我们使用了小干扰 RNA (siRNA) 介导的敲低。与 μ1 表达减少中观察到的情况类似，新合成的 σ3 的敲低会增强坏死性凋亡。敲除 σ3 不会影响呼肠孤病毒 RNA 合成。相反，σ3 敲低后坏死性凋亡的增加伴随着 IFN 产量的增加。此外，σ3 的异位表达足以阻断感染后的 IFN 表达。令人惊讶的是，σ3 蛋白结合 dsRNA 的能力不会影响其减少 IFN 产生的能力。与此一致的是，感染 σ3 dsRNA 结合域突变的病毒不会导致 IFN 产生增加或坏死性凋亡。总之，这些数据表明，σ3 通过一种独立于 dsRNA 结合能力的机制，限制了 IFN 的产生，从而控制先天免疫信号传导和感染后的坏死性凋亡。重要性我们使用哺乳动物呼肠孤病毒作为模型来研究病毒感染如何调节先天免疫信号传导和细胞死亡诱导。在这里，我们试图确定病毒因素如何调节这些过程。我们的工作强调了呼肠孤病毒外衣壳蛋白 σ3 在限制诱导坏死性细胞死亡（称为坏死性凋亡）方面的先前未知的作用。通过坏死性凋亡诱导细胞死亡需要产生干扰素。 σ3 蛋白通过防止感染后干扰素的过量产生来限制坏死性凋亡的诱导。
Induction of necroptosis by mammalian reovirus requires both type I interferon (IFN)-signaling and viral replication events that lead to production of progeny genomic double-stranded RNA (dsRNA). The reovirus outer capsid protein μ1 negatively regulates reovirus-induced necroptosis by limiting RNA synthesis. To determine if the outer capsid protein σ3, which interacts with μ1, also functions in regulating necroptosis, we used small interfering RNA (siRNA)-mediated knockdown. Similarly to what was observed in diminishment of μ1 expression, knockdown of newly synthesized σ3 enhances necroptosis. Knockdown of σ3 does not impact reovirus RNA synthesis. Instead, this increase in necroptosis following σ3 knockdown is accompanied by an increase in IFN production. Furthermore, ectopic expression of σ3 is sufficient to block IFN expression following infection. Surprisingly, the capacity of σ3 protein to bind dsRNA does not impact its capacity to diminish production of IFN. Consistent with this, infection with a virus harboring a mutation in the dsRNA binding domain of σ3 does not result in enhanced production of IFN or necroptosis. Together, these data suggest that σ3 limits the production of IFN to control innate immune signaling and necroptosis following infection through a mechanism that is independent of its dsRNA binding capacity.IMPORTANCEWe use mammalian reovirus as a model to study how virus infection modulates innate immune signaling and cell death induction. Here, we sought to determine how viral factors regulate these processes. Our work highlights a previously unknown role for the reovirus outer capsid protein σ3 in limiting the induction of a necrotic form of cell death called necroptosis. Induction of cell death by necroptosis requires production of interferon. The σ3 protein limits the induction of necroptosis by preventing excessive production of interferon following infection.