Human IFIT3 Protein Induces Interferon Signaling and Inhibits Adenovirus Immediate Early Gene Expression.
Human IFIT3 Protein Induces Interferon Signaling and Inhibits Adenovirus Immediate Early Gene Expression.
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DOI：
10.1128/mbio.02829-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Hearing P
中科院分区：
文献类型：
--
作者：
Chikhalya A;Dittmann M;Zheng Y;Sohn SY;Rice CM;Hearing P
干扰素（IFN）是宿主抗病毒免疫的标志之一。干扰素通过诱导干扰素刺激基因（ISGs）和抗病毒蛋白发挥其抗病毒活性;然而，ISGs抑制腺病毒（Ad）复制的机制尚不清楚。IFN抑制Ad立即早期基因表达，并因此抑制病毒生命周期的所有后续方面。在本研究中，我们发现IFN诱导的蛋白与tetratricopeptide repeats 3，IFIT 3（ISG 60），限制广告复制。IFIT 3抑制Ad E1 A立即早期基因表达，但不改变Ad基因组进入细胞核。IFIT 3的表达导致TBK 1、IRF 3和STAT 1的磷酸化; IFNβ和ISG的表达增加;并且需要IFIT 1和IFIT 2伴侣蛋白。在RNA病毒感染期间，已知IFIT 3通过线粒体抗病毒信号传导（MAVS）介导的TBK 1的活化刺激IFN产生，TBK 1协同IRF 3和NF-κB的活化。表达IFIT 3的细胞中的MAVS或TBK 1缺失阻断IFN信号传导并逆转Ad复制限制。此外，STING耗竭表型模拟了该效应，表明IFIT 3激活STING途径，与MAVS途径有串扰。这与病毒病原体相关分子模式（PAMP）无关。这些结果表明，单个ISG IFIT 3的表达激活IFN信号传导并建立不依赖于病毒PAMP的细胞抗病毒状态。
Interferons (IFNs) are one of the hallmarks of host antiviral immunity. IFNs exert their antiviral activities through the induction of IFN-stimulated genes (ISGs) and antiviral proteins; however, the mechanism by which ISGs inhibit adenovirus (Ad) replication is not clearly understood. IFNs repress Ad immediate early gene expression and, consequently, all subsequent aspects of the viral life cycle. In this study, we found that IFN-induced protein with tetratricopeptide repeats 3, IFIT3 (ISG60), restricts Ad replication. IFIT3 repressed Ad E1A immediate early gene expression but did not alter Ad genome entry into the nucleus. Expression of IFIT3 led to phosphorylation of TBK1, IRF3, and STAT1; increased expression of IFNβ and ISGs; and required IFIT1 and IFIT2 partner proteins. During RNA virus infections, it is known that IFIT3 stimulates IFN production through mitochondrial antiviral signaling (MAVS)-mediated activation of TBK1 which synergizes activation of IRF3 and NF-κB. MAVS or TBK1 depletion in cells expressing IFIT3 blocked IFN signaling and reversed the Ad replication restriction. In addition, STING depletion phenocopied the effect suggesting that IFIT3 activates the STING pathway with cross talk to the MAVS pathway. This occurs independently of viral pathogen-associated molecular patterns (PAMPs). These results demonstrate that the expression of a single ISG, IFIT3, activates IFN signaling and establishes a cellular antiviral state independent of viral PAMPs.