IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation.
IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation.
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IRF3抑制NF-κB核易位，预防病毒炎症。
DOI：
10.1073/pnas.2121385119
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发表时间：
2022-09-13
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
先天免疫反应是抵御入侵病原体的第一道防线。病毒感染迅速激活细胞内信号通路，导致抗病毒和炎症反应。炎症反应有利于对病毒感染的早期保护，而无节制的炎症反应则对宿主有害。我们报道了一种抑制病毒诱导的炎症基因表达的细胞抗炎机制。利用细胞和小鼠模型，我们揭示了IRF3，先天抗病毒免疫的关键成分，抑制了促炎转录因子NF-κB的活性。在机制上，IRF3结合了NF-κB-p65亚单位，并阻止其移位到细胞核。因此，我们似乎已经发现了以前未知的IRF3在调节病毒炎症中的功能。干扰素调节因子3是一种转录因子，在病毒感染细胞的胞浆中被磷酸化激活，通过转位到细胞核，诱导干扰素-β和其他抗病毒基因的转录。我们以前已经报道过，IRF3也可以被RIG-I途径介导的线性泛素化激活，作为一种促凋亡因子。IRF3的转录和凋亡功能与其抗病毒作用有关。在这里，我们报道了IRF3的一个非转录功能，即抑制IRF3介导的NF-κB活性(RiKA)，从而减弱病毒对NF-κB的激活和由此产生的炎症基因的诱导。因此，在irf3−/−小鼠中，仙台病毒感染导致肺部炎症加剧。从机制上讲，RiKA是通过IRF3与胞浆中的NF-κB的p65亚基直接结合而介导的，从而阻止了它的核输入。突变的IRF3在转录和凋亡活性上都存在缺陷，在Rika中表现活跃，并抑制病毒的复制。我们的结果表明，IRF3对病毒复制和伴随的炎症进行了三管齐下的攻击。
The innate immune response is the first line of defense against invading pathogens. Virus infection rapidly activates the intracellular signaling pathways, resulting in antiviral and inflammatory responses. The inflammatory response is beneficial for the early protection against the virus infection; however, unregulated inflammation is harmful to the host. We report a cellular antiinflammatory mechanism that inhibits the virus-induced inflammatory gene expression. Using cellular and mouse models, we reveal IRF3, a critical component of innate antiviral immunity, inhibits the activity of NF-κB, the pro-inflammatory transcription factor. Mechanistically, IRF3 binds the NF-κB–p65 subunit and prevents its translocation to the nucleus. It appears, therefore, that we have uncovered a previously unknown function for IRF3 in regulating viral inflammation. Interferon (IFN) regulatory factor 3 (IRF3) is a transcription factor activated by phosphorylation in the cytoplasm of a virus-infected cell; by translocating to the nucleus, it induces transcription of IFN-β and other antiviral genes. We have previously reported IRF3 can also be activated, as a proapoptotic factor, by its linear polyubiquitination mediated by the RIG-I pathway. Both transcriptional and apoptotic functions of IRF3 contribute to its antiviral effect. Here, we report a nontranscriptional function of IRF3, namely, the repression of IRF3-mediated NF-κB activity (RIKA), which attenuated viral activation of NF-κB and the resultant inflammatory gene induction. In Irf3−/− mice, consequently, Sendai virus infection caused enhanced inflammation in the lungs. Mechanistically, RIKA was mediated by the direct binding of IRF3 to the p65 subunit of NF-κB in the cytoplasm, which prevented its nuclear import. A mutant IRF3 defective in both the transcriptional and the apoptotic activities was active in RIKA and inhibited virus replication. Our results demonstrated IRF3 deployed a three-pronged attack on virus replication and the accompanying inflammation.
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