Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association.
Mitochondrial DUT-M potentiates RLR-mediated antiviral signaling by enhancing VISA and TRAF2 association.
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DOI：
10.1016/j.molimm.2021.01.023
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发表时间：
2021-02
影响因子：
3.6
通讯作者：
Guang‐Xiu Weng;T. Ling;Wen Hou;Sheng‐Na Li;Tian Chen;Zhi Zhang;Dandan Wang;Liang-Guo Xu
中科院分区：
文献类型：
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作者：
Guang‐Xiu Weng;T. Ling;Wen Hou;Sheng‐Na Li;Tian Chen;Zhi Zhang;Dandan Wang;Liang-Guo Xu
在识别胞质内病毒RNA后，激活的RIG-I被募集到位于外显子的接头蛋白VISA（也称为MAVS、CARDIF和IPS-1）。然后VISA作为连接RIG-I和下游信号传导组分（如TRAF 2、5和6、TBK 1和IKK）的中心信号传导平台，导致激酶TBK 1和IKK的活化。这些活化的激酶进一步磷酸化转录因子IRF 3/7和NF-κB，导致下游抗病毒基因的诱导。在这里，我们报告的线粒体亚型，脱氧尿苷三磷酸核苷酸水解酶（dUTH），DUT-M，作为一个积极的调节RLR-VISA介导的抗病毒信号。DUT-M与VISA和RIG-I相互作用，以促进VISA-TRAF 2复合物的组装，并增强TRAF 2的多聚泛素化，从而增强IRF 3二聚化和P65磷酸化的激活，并增强VISA介导的先天免疫应答。RLR-VISA介导的IRF 3二聚化和P65磷酸化在DUT敲低和DUT缺陷的293细胞中被抑制。因此，DUT-M是RIG-I-VISA介导的对RNA病毒的先天免疫应答的正调节剂。
Upon recognition of intracytoplasmic viral RNA, activated RIG-I is recruited to the mitochondrion-located adaptor protein VISA (also known as MAVS, CARDIF, and IPS-1). VISA then acts as a central signaling platform for linking RIG-I and downstream signaling components, such as TRAF2, 5, and 6, TBK1, and IKK, leading to activation of the kinases TBK1 and IKK. These activated kinases further phosphorylate the transcription factors IRF3/7 and NF-κB, leading to the induction of downstream antiviral genes. Here, we report a mitochondrial isoform, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), DUT-M, as a positive regulator in RLR-VISA-mediated antiviral signaling. DUT-M interacts with VISA and RIG-I to facilitate the assembly of the VISA-TRAF2 complex and to augment the polyubiquitination of TRAF2, leading to potentiated activation of IRF3 dimerization and phosphorylation of P65, and enhanced VISA-mediated innate immune response. RLR-VISA-mediated IRF3 dimerization and P65 phosphorylation, were inhibited in DUT-knockdown and DUT-deficient 293 cells. Thus, DUT-M is a positive regulator of the RIG-I-VISA-mediated innate immune response to RNA viruses.