The OAS-RNase L pathway is one of the oldest innate RNA sensing pathways that leads to interferon (IFN) signaling and cell death. OAS recognizes viral RNA and then activates RNase L, which subsequently cleaves both cellular and viral RNA, creating "processed RNA" as an endogenous ligand that further triggers RIG-I-like receptor signaling. However, the IFN response and antiviral activity of the OAS-RNase L pathway are weak compared to other RNA-sensing pathways. Here, we discover that the SKIV2L RNA exosome limits the antiviral capacity of the OAS-RNase L pathway. SKIV2L-deficient cells exhibit remarkably increased interferon responses to RNase L-processed RNA, resulting in heightened antiviral activity. The helicase activity of SKIV2L is indispensable for this function, acting downstream of RNase L. SKIV2L depletion increases the antiviral capacity of OAS-RNase L against RNA virus infection. Furthermore, SKIV2L loss exacerbates autoinflammation caused by human OAS1 gain-of-function mutations. Taken together, our results identify SKIV2L as a critical barrier to OAS-RNase L-mediated antiviral immunity that could be therapeutically targeted to enhance the activity of a basic antiviral pathway.

中文翻译：

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RNA 解旋酶 SKIV2L 限制 OAS-RNase L 途径引起的抗病毒防御和自身炎症。


OAS-RNase L 通路是最古老的先天 RNA 传感通路之一，可导致干扰素 (IFN) 信号传导和细胞死亡。 OAS 识别病毒 RNA，然后激活 RNase L，随后裂解细胞和病毒 RNA，产生“加工过的 RNA”作为内源配体，进一步触发 RIG-I 样受体信号传导。然而，与其他 RNA 传感途径相比，OAS-RNase L 途径的 IFN 反应和抗病毒活性较弱。在这里，我们发现 SKIV2L RNA 外泌体限制了 OAS-RNase L 途径的抗病毒能力。 SKIV2L 缺陷细胞对 RNase L 加工的 RNA 表现出显着增强的干扰素反应，从而导致抗病毒活性增强。 SKIV2L 的解旋酶活性对于该功能是不可或缺的，作用于 RNase L 的下游。SKIV2L 耗竭会增加 OAS-RNase L 对抗 RNA 病毒感染的抗病毒能力。此外，SKIV2L 缺失会加剧人类 OAS1 功能获得性突变引起的自身炎症。综上所述，我们的结果确定 SKIV2L 是 OAS-RNase L 介导的抗病毒免疫的关键屏障，可以在治疗上靶向增强基本抗病毒途径的活性。