Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
Mol Immunol. 2019 Oct;114:330-340. doi: 10.1016/j.molimm.2019.08.007. Epub 2019 Aug 21.
We previously reported that some small interfering RNA (siRNA) enhances DNA or DNA virus mediated-interferon (IFN)-λ1(a type III IFN) induction through the crosstalk between retinoic acid-inducible gene I (RIG-I) and interferon gamma-inducible protein 16 (IFI16) signalling pathway. Here we provide further evidence of a new role for siRNA. siRNA containing a 5-nucleotide (nt) motif sequence suppresses DNA-mediated not only type III IFNs, but also type I IFNs and inflammatory cytokines. We define that motif siRNA inhibits the induction when the motif is located at the 3' or 5'-terminus of siRNA. Using THP1-Lucia ISG cells with various DNA stimulants, we reveal that motif siRNA inhibits DNA or DNA virus but not RNA virus-mediated signalling. Motif siRNA specifically interrupts IFI16 but not cyclic GMP-AMP synthase (cGAS) binding to DNA and has 2.5-fold higher affinity to IFI16 than that of siRNA without the motif. We further confirm that motif siRNA potently suppresses HSV-1 virus-mediated IFNs and inflammatory cytokines, such as IFNL1, IFNB and TNFA, in human primary immature dendritic cells. Collectively, these findings may shed light on a novel function of siRNA with the unique 5-nt motif as a quencher of innate immunity and facilitate the development of potential therapeutics to regulate innate immune cascades.
我们之前报道了一些小干扰 RNA（siRNA）通过视黄酸诱导基因 I（RIG-I）和干扰素 γ 诱导蛋白 16（IFI16）信号通路之间的串扰增强 DNA 或 DNA 病毒介导的干扰素（IFN）-λ1（一种 III 型 IFN）的诱导。在这里，我们提供了 siRNA 的新作用的进一步证据。含有 5 个核苷酸（nt）基序序列的 siRNA 不仅抑制 DNA 介导的 III 型 IFN，还抑制 I 型 IFN 和炎症细胞因子。我们定义该基序 siRNA 在基序位于 siRNA 的 3' 或 5' 末端时抑制诱导。使用具有各种 DNA 刺激物的 THP1-Lucia ISG 细胞，我们揭示基序 siRNA 抑制 DNA 或 DNA 病毒但不抑制 RNA 病毒介导的信号。基序 siRNA 特异性中断 IFI16 而不是环鸟苷酸-AMP 合酶（cGAS）与 DNA 的结合，并且与没有基序的 siRNA 相比，对 IFI16 的亲和力高 2.5 倍。我们进一步证实，基序 siRNA 能够强烈抑制 HSV-1 病毒介导的 IFNs 和炎症细胞因子，如 IFNL1、IFNB 和 TNFA，在人原代未成熟树突状细胞中。总之，这些发现可能揭示了 siRNA 的一种新功能，具有独特的 5-nt 基序作为先天免疫的猝灭剂，并有助于开发潜在的治疗方法来调节先天免疫级联反应。
