Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59801, USA.
Division of Biological Sciences, University of Montana, Missoula, MT 59801, USA.
Viruses. 2023 Jul 18;15(7):1566. doi: 10.3390/v15071566.
Although the noncanonical NFκB pathway was originally identified as a cellular pathway contributing to lymphoid organogenesis, in the past 20 years, its involvement in innate immunity has become more appreciated. In particular, the noncanonical NFκB pathway has been found to be activated and even exploited by some RNA viruses during infection. Intriguingly, activation of this pathway has been shown to have a role in disrupting transcription of type 1 interferon (IFN), suggesting a rationale for why this response could be co-opted by some viruses. Rift Valley fever virus (RVFV) is a trisegmented ambisense RNA virus that poses a considerable threat to domestic livestock and human health. Previously, we showed the atypical kinase RIOK3 is important for mounting an IFN response to RVFV infection of human epithelial cells, and shortly following infection with RVFV (MP12 strain), RIOK3 mRNA is alternatively spliced to its X2 isoform that encodes a truncated RIOK3 protein. Alternative splicing of RIOK3 mRNA has an inhibitory effect on the IFN response but also stimulates an NFκB-mediated inflammatory response. Here, we demonstrate alternative splicing of RIOK3 mRNA is associated with activation of the noncanonical NFκB pathway and suggest this pathway is co-opted by RVFV (MP12) to enhance viral success during infection.
尽管非典型性 NFκB 通路最初被鉴定为参与淋巴器官发生的细胞通路，但在过去的 20 年中，其在先天免疫中的作用得到了更多的认识。特别是，已经发现一些 RNA 病毒在感染期间会激活甚至利用非典型性 NFκB 通路。有趣的是，该通路的激活已被证明在破坏 I 型干扰素（IFN）的转录中起作用，这表明了为什么这种反应可能被某些病毒利用的合理依据。裂谷热病毒（RVFV）是一种三片段反义 RNA 病毒，对家畜和人类健康构成了相当大的威胁。此前，我们表明非典型激酶 RIOK3 对于人上皮细胞感染 RVFV 时的 IFN 反应至关重要，并且在感染 RVFV（MP12 株）后不久，RIOK3 mRNA 就会被剪接为其 X2 异构体，该异构体编码一个截断的 RIOK3 蛋白。RIOK3 mRNA 的选择性剪接对 IFN 反应具有抑制作用，但也会刺激 NFκB 介导的炎症反应。在这里，我们证明 RIOK3 mRNA 的选择性剪接与非典型性 NFκB 通路的激活有关，并表明该通路被 RVFV（MP12）利用来增强感染期间的病毒成功。
