Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses
Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses
复制标题
介导抗病毒先天免疫反应的核孔蛋白 93 (Nup93) 的鉴定
DOI：
10.1016/j.bbrc.2019.11.035
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发表时间：
2020
影响因子：
3.1
通讯作者：
Kawai Taro
中科院分区：
文献类型：
--
作者：
Monwan Warunthorn;Kawasaki Takumi;Hasan Md Zobaer;Ori Daisuke;Kawai Taro
RIG-I样受体（RLR）是病毒RNA的细胞质传感器，其引发抗病毒先天免疫应答。RLR信号传导在蛋白激酶TBK 1的活化中达到高潮，TBK 1介导IRF 3的磷酸化和核转位，IRF 3调节I型干扰素基因的表达。核孔蛋白93（Nucleoporin 93，Nup 93）是核孔复合物（Nuclear pore complex，NPC）的组成部分，在TLR介导的抗病毒反应中起重要作用。NUP 93缺陷的RAW264.7巨噬细胞在用合成的RLR激动剂刺激以及纽卡斯尔病病毒感染处理后表现出Ifnb 1和Cxcl 10基因表达的降低。在小鼠原代巨噬细胞和胚胎成纤维细胞中沉默Nup 93也导致这些基因的表达减少。在Nup 93缺陷的RAW264.7细胞中，RLR信号传导过程中的IRF 3核转位受损。值得注意的是，在Nup 93缺陷细胞中，RLR信号传导期间TBK 1的活化也减少。我们发现Nup 93与TBK 1形成复合物，并且Nup 93过表达增强TBK 1介导的IFNβ启动子激活。总之，我们的研究结果表明，Nup 93通过增强TBK 1活性和IRF 3核转位来调节抗病毒先天免疫。
RIG-I-like receptors (RLRs) are cytoplasmic sensors for viral RNA that elicit antiviral innate immune responses. RLR signaling culminates in the activation of the protein kinase TBK1, which mediates phosphorylation and nuclear translocation of IRF3 that regulates expression of type I interferon genes. Here, we found that Nucleoporin 93 (Nup93), components of nuclear pore complex (NPC), plays an important role in RLR-mediated antiviral responses. Nup93-deficient RAW264.7 macrophage cells exhibited decreased expression ofIfnb1andCxcl10genes after treatment with a synthetic RLR agonist stimulation as well as Newcastle Disease Virus infection. Silencing Nup93 in murine primary macrophages and embryonic fibroblasts also resulted in reduced expression of these genes. IRF3 nuclear translocation during RLR signaling was impaired in Nup93-deficient RAW264.7 cells. Notably, the activation of TBK1 during RLR signaling was also decreased in Nup93-deficient cells. We found that Nup93 formed a complex with TBK1, and Nup93 overexpression enhanced TBK1-mediated IFNβ promoter activation. Taken together, our findings suggest that Nup93 regulates antiviral innate immunity by enhancing TBK1 activity and IRF3 nuclear translocation.