The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity.
The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity.
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DOI：
10.1186/s12985-014-0209-9
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发表时间：
2014-12-07
期刊：
影响因子：
4.8
通讯作者：
Frieman M
中科院分区：
文献类型：
--
作者：
Matthews K;Schäfer A;Pham A;Frieman M
病毒感染的结果是由病毒和宿主因子的复杂相互作用调节的。SARS冠状病毒（SARS-CoV）在感染过程中参与并调节几种先天免疫反应途径。我们先前已经表明SARS-CoV木瓜蛋白酶样蛋白酶（PLpro）通过抑制IRF 3磷酸化从而阻断下游干扰素诱导来抑制I型干扰素（IFN）。这一发现促使我们确定PLpro抑制IFN诱导的其他潜在机制。我们使用了表达PLpro和IRF 3的质粒，包括组成型活性的IRF 3突变体，称为IRF 3（5D）。在这些实验中，我们利用转染、染色质免疫沉淀、电迁移率改变测定（EMSA）和蛋白定位来鉴定IRF 3和IRF 3（5D）被PLpro抑制的位置。在这里，我们表明，PLpro也抑制IRF 3激活磷酸化后的一个步骤，这种抑制是依赖于去泛素化（DUB）PLpro的活动。我们发现PLpro能够阻断I型IFN诱导组成型活性IRF 3，但不抑制IRF 3二聚化、核定位或DNA结合。然而，通过诱变抑制PLpro的DUB活性阻断了PLpro的IRF 3抑制活性，表明IRF 3泛素化在诱导I型IFN先天免疫应答中的作用。这些结果证明了PLpro能够抑制IRF 3信号传导的另外的机制。这些数据表明PLpro的新的先天免疫拮抗活性可能有助于SARS-CoV的发病机制。
The outcome of a viral infection is regulated by complex interactions of viral and host factors. SARS coronavirus (SARS-CoV) engages and regulates several innate immune response pathways during infection. We have previously shown that the SARS-CoV Papain-like Protease (PLpro) inhibits type I interferon (IFN) by inhibiting IRF3 phosphorylation thereby blocking downstream Interferon induction. This finding prompted us to identify other potential mechanisms of inhibition of PLpro on IFN induction. We have used plasmids expressing PLpro and IRF3 including an IRF3 mutant that is constitutively active, called IRF3(5D). In these experiments we utilize transfections, chromatin immunoprecipitation, Electro-mobility Shift Assays (EMSA) and protein localization to identify where IRF3 and IRF3(5D) are inhibited by PLpro. Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. These results demonstrate an additional mechanism that PLpro is able to inhibit IRF3 signaling. These data suggest novel innate immune antagonism activities of PLpro that may contribute to SARS-CoV pathogenesis.
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影响因子：
5.4
作者：
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通讯作者：
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DOI：
10.1073/pnas.0603144103
发表时间：
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影响因子：
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作者：
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