Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped Virions
Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped Virions
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DOI：
10.1128/jvi.80.1.226-235.2006
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发表时间：
2006-01-01
影响因子：
5.4
通讯作者：
Mossman, KL
中科院分区：
文献类型：
--
作者：
Noyce, RS;Collins, SE;Mossman, KL
病毒感染引起许多细胞信号转导通路的激活，导致先天免疫和获得性免疫的诱导。此前，我们发现，在没有干扰素产生的情况下，来自不同包膜病毒家族的病毒粒子进入人成纤维细胞能够诱导干扰素调节因子3(IRF-3)介导的抗病毒状态。在这里，我们表明，细胞外调节蛋白激酶1/2、p38丝裂原活化蛋白激酶和Jun氨基末端激酶/应激激活蛋白激酶活性不是诱导抗病毒状态所必需的。相比之下，用磷脂酰肌醇3-激酶(P13激酶)家族的抑制剂LY294002处理细胞，可以防止干扰素刺激基因56(ISG56)的诱导和病毒颗粒进入时的抗病毒反应。然而，Ip85/p110P13蛋白及其下游效应蛋白Akt/PKB对于诱导ISG和抗病毒状态是必不可少的。此外，DNA-PK和PKI，LY294002敏感的P13激酶家族成员，以前被证明参与了IRF-3的激活，对于ISG和抗病毒状态的诱导也是必不可少的。LY294002抑制剂不能阻止IRF-3同源二聚化或病毒颗粒进入时的核转位。综上所述，这些数据表明，病毒进入触发了一种先天的抗病毒反应，这需要一个新的P13激酶家族成员的活性。
Viral infection elicits the activation of numerous cellular signal transduction pathways, leading to the induction of both innate and adaptive immunity. Previously we showed that entry of virion particles from a diverse array of enveloped virus families was capable of eliciting an interferon regulatory factor 3 (IRF-3)-mediated antiviral state in human fibroblasts in the absence of interferon production. Here we show that extracellular regulated kinase 1/2, p38 mitogen-activated protein kinase, and Jun N-terminal kinase/stressactivated protein kinase activities are not required for antiviral state induction. In contrast, treatment of cells with LY294002, an inhibitor of the phosphoinositide 3-kinase (P13 kinase) family, prevents the induction of interferon-stimulated gene 56 (ISG56) and an antiviral response upon entry of virus particles. However, the prototypic class I p85/p110 P13 kinase and its downstream effector Akt/PKB are dispensable for ISG and antiviral state induction. Furthermore, DNA-PK and PAKI, LY294002-sensitive members of the P13 kinase family shown previously to be involved in IRF-3 activation, are also dispensable for ISG and antiviral state induction. The LY294002 inhibitor fails to prevent IRF-3 homodimerization or nuclear translocation upon virus particle entry. Together, these data suggest that virus entry triggers an innate antiviral response that requires the activity of a novel P13 kinase family member.