Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.
Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus.
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DOI：
10.1074/jbc.m704870200
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发表时间：
2007-11-02
期刊：
影响因子：
--
通讯作者：
Li K
中科院分区：
文献类型：
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作者：
Devaraj SG;Wang N;Chen Z;Chen Z;Tseng M;Barretto N;Lin R;Peters CJ;Tseng CT;Baker SC;Li K
严重急性呼吸综合征冠状病毒（SARS-CoV）是一种新型冠状病毒，可引起高度传染性的呼吸道疾病SARS，具有显著的死亡率。尽管对SARS-CoV高致病性的因素仍然知之甚少，但据报道，SARS-CoV感染不会在细胞培养中诱导I型干扰素（IFN）。然而，目前还不确定SARS-CoV是否能逃避宿主检测，或者是否已经进化出了抵消宿主先天防御的机制。我们在这里表明，SARS冠状病毒感染引发弱IFN反应在培养的人肺/支气管上皮细胞，而不诱导IFN-调节因子3（IRF-3），一个潜在的细胞转录因子，是关键的I型IFN合成的磷酸化。此外，SARS-CoV感染阻断了IFN抗病毒活性的诱导和由双链RNA或不相关的副粘病毒触发的IFN刺激基因的子集的蛋白质表达的上调。在寻找能够对抗先天免疫的SARS-CoV蛋白时，我们鉴定了木瓜蛋白酶样蛋白酶（PLpro）结构域作为有效的IFN拮抗剂。IFN应答的抑制不需要PLpro的蛋白酶活性。相反，PLpro与IRF-3相互作用并抑制IRF-3的磷酸化和核转位，从而破坏通过Toll样受体3或视黄酸诱导基因I/黑色素瘤分化相关基因5途径激活的I型IFN应答。我们的数据表明PLpro对IRF-3依赖的先天性抗病毒防御的调节可能有助于SARS-CoV感染的建立。
Severe acute respiratory syndrome coronavirus (SARS-CoV) is a novel coronavirus that causes a highly contagious respiratory disease, SARS, with significant mortality. Although factors contributing to the highly pathogenic nature of SARS-CoV remain poorly understood, it has been reported that SARS-CoV infection does not induce type I interferons (IFNs) in cell culture. However, it is uncertain whether SARS-CoV evades host detection or has evolved mechanisms to counteract innate host defenses. We show here that infection of SARS-CoV triggers a weak IFN response in cultured human lung/bronchial epithelial cells without inducing the phosphorylation of IFN-regulatory factor 3 (IRF-3), a latent cellular transcription factor that is pivotal for type I IFN synthesis. Furthermore, SARS-CoV infection blocked the induction of IFN antiviral activity and the up-regulation of protein expression of a subset of IFN-stimulated genes triggered by double-stranded RNA or an unrelated paramyxovirus. In searching for a SARS-CoV protein capable of counteracting innate immunity, we identified the papain-like protease (PLpro) domain as a potent IFN antagonist. The inhibition of the IFN response does not require the protease activity of PLpro. Rather, PLpro interacts with IRF-3 and inhibits the phosphorylation and nuclear translocation of IRF-3, thereby disrupting the activation of type I IFN responses through either Toll-like receptor 3 or retinoic acid-inducible gene I/melanoma differentiation-associated gene 5 pathways. Our data suggest that regulation of IRF-3-dependent innate antiviral defenses by PLpro may contribute to the establishment of SARS-CoV infection.