The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1-IRF3 signaling
The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1-IRF3 signaling
复制标题
甲基转移酶 PRMT6 通过阻断 TBK1-IRF3 信号传导减弱抗病毒先天免疫
DOI：
10.1038/s41423-018-0057-4
复制
发表时间：
2019-10-01
影响因子：
24.1
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Zhang, Hua;Han, Chaofeng;Cao, Xuetao
蛋白质精氨酸甲基转移酶（PRMT）发挥着多种生物学作用，特别是参与免疫细胞发育和炎症。然而，它们在抗病毒先天免疫中的作用尚未阐明。病毒感染触发TBK 1-IRF 3信号通路以刺激介导抗病毒免疫的I型干扰素的产生。我们对9种哺乳动物PRMTs进行了IFN-β表达调节因子的功能筛选，发现PRMT 6抑制抗病毒先天免疫应答。病毒感染也上调PRMT 6蛋白水平。我们产生了PRMT 6缺陷小鼠，发现它们表现出增强的抗病毒先天免疫。PRMT 6缺陷促进TBK 1-IRF 3相互作用，随后增强IRF 3活化和I型干扰素产生。从机制上讲，病毒感染增强了PRMT 6与IRF 3的结合，并抑制了IRF 3与TBK 1之间的相互作用;这种机制与PRMT 6甲基转移酶活性无关。因此，PRMT 6通过隔离IRF 3来抑制抗病毒先天免疫，从而阻断TBK 1-IRF 3信号传导。我们的工作证明了PRMT的甲基转移酶独立作用。它还确定了抗病毒免疫应答的负调节因子，其可以保护宿主免受过度活跃的免疫系统的破坏性影响和/或被病毒利用以逃避免疫检测。
Protein arginine methyltransferases (PRMTs) play diverse biological roles and are specifically involved in immune cell development and inflammation. However, their role in antiviral innate immunity has not been elucidated. Viral infection triggers the TBK1-IRF3 signaling pathway to stimulate the production of type-I interferon, which mediates antiviral immunity. We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-beta expression and found that PRMT6 inhibits the antiviral innate immune response. Viral infection also upregulated PRMT6 protein levels. We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity. PRMT6 deficiency promoted the TBK1-IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production. Mechanistically, viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1; this mechanism was independent of PRMT6 methyltransferase activity. Thus, PRMT6 inhibits antiviral innate immunity by sequestering IRF3, thereby blocking TBK1-IRF3 signaling. Our work demonstrates a methyltransferase-independent role for PRMTs. It also identifies a negative regulator of the antiviral immune response, which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.