A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction
A Kaposi's Sarcoma-Associated Herpesvirus Protein That Forms Inhibitory Complexes with Type I Interferon Receptor Subunits, Jak and STAT Proteins, and Blocks Interferon-Mediated Signal Transduction
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DOI：
10.1128/jvi.02516-08
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发表时间：
2009-05-15
影响因子：
5.4
通讯作者：
Ganem, Don
中科院分区：
文献类型：
--
作者：
Bisson, Sabine A.;Page, Anne-Laure;Ganem, Don
I型干扰素(IFN)通过其同源I型受体(IFNAR)激活信号通路，是天然抗病毒防御和功能的重要介体。在这里，我们报道了Kaposi肉瘤相关疱疹病毒(KSHV)的裂解复制有效地阻断了I型干扰素信号，这种阻断的一个重要效应是病毒蛋白RIF，它是开放阅读框架10的产物。RIF通过形成包含IFNAR亚单位、Janus激酶JAK1和TYK2以及STAT2转录因子的抑制复合体来阻断干扰素信号。TYK2和JAK1的激活都受到抑制，尽管TYK2活性降低，但STAT2异常募集到IFNAR1。这些作用的结果是，STAT2和STAT1的磷酸化都受到了损害，随后ISGF3在细胞核中的积累失败。在病毒基因组中存在有效的I型干扰素信号抑制因子，以及几个阻断干扰素诱导的病毒基因，突显了干扰素途径在控制这种人类肿瘤病毒感染方面的重要性。
Type I interferons (IFNs) are important mediators of innate antiviral defense and function by activating a signaling pathway through their cognate type I receptor (IFNAR). Here we report that lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) efficiently blocks type I IFN signaling and that an important effector of this blockade is the viral protein RIF, the product of open reading frame 10. RIF blocks IFN signaling by formation of inhibitory complexes that contain IFNAR subunits, the Janus kinases Jak1 and Tyk2, and the STAT2 transcription factor. Activation of both Tyk2 and Jak1 is inhibited, and abnormal recruitment of STAT2 to IFNAR1 occurs despite the decrement in Tyk2 activity. As a result of these actions, phosphorylation of both STAT2 and STAT1 is impaired, with subsequent failure of ISGF3 accumulation in the nucleus. The presence in the viral genome of potent inhibitors of type I IFN signaling, along with several viral genes that block IFN induction, highlights the importance of the IFN pathway in the control of this human tumor virus infection.