1. RNA helicase SKIV2L limits antiviral defense and autoinflammation elicited by the OAS-RNase L pathway.
- Author
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Yang, Kun, Dong, Beihua, Asthana, Abhishek, Silverman, Robert H, and Yan, Nan
- Abstract
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. Synopsis: The antiviral activity of the OAS-RNase L pathway is weaker than that of other RNA-sensing pathways. This study shows a moderating effect of the SKIV2L cytoplasmic RNA exosome, which degrades the immunogenic RNA produced by RNase L. The SKIV2L cytoplasmic RNA exosome limits the dsRNA-induced innate immune response. The RNA helicase activity of SKIV2L is essential for this effect. SKIV2L acts selectively downstream of RNase L in the OAS-RNase L pathway. SKIV2L loss exacerbates autoinflammation caused by human OAS1 gain-of-function mutations. The helicase activity of SKIV2L acts downstream of RNase L to reduce the immunogenic output of the OAS-RNase L pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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