Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses.
Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses.
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DOI：
10.1371/journal.ppat.1003416
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Lamarre D
中科院分区：
文献类型：
--
作者：
Baril M;Es-Saad S;Chatel-Chaix L;Fink K;Pham T;Raymond VA;Audette K;Guenier AS;Duchaine J;Servant M;Bilodeau M;Cohen E;Grandvaux N;Lamarre D
为了确定抗病毒先天免疫的新调节因子，我们完成了第一个全基因组基因沉默筛选，评估仙台病毒（SeV）感染后干扰素-β（IFNB 1）启动子的转录反应。我们现在报告一个新的WNT信号通路和视黄酸诱导基因I（RIG-I）样受体（RLR）依赖的先天免疫反应的调制之间的联系。在这里，我们表明，分泌的WNT 2B和WNT 9 B和稳定的β-连环蛋白（CTNNB 1）病毒感染后负调控的表达的代表性诱导基因IFNB 1，IFIT 1和TNF的CTNNB 1依赖性效应机制。抗病毒反应被糖原合成酶激酶3（GSK 3）抑制剂显著降低，但在CTNNB 1敲低细胞中恢复。这些发现证实了一种新的调节抗病毒先天免疫的经典样WNT/CTNNB 1信号通路。该研究确定了广谱抗病毒靶点和预防病毒感染后免疫介导疾病的新途径。先天免疫系统是具有适应性免疫系统的生物体的第一道防线。它允许在病毒感染时快速免疫应答，除了在邻近细胞中传播抗病毒状态之外。为了鉴定参与抗病毒反应的新蛋白质，我们通过单独沉默15，000个人类基因的表达来完成第一个全基因组RNA干扰（RNAi）筛选，以评估它们在仙台病毒（SeV）感染后诱导I型干扰素-β（IFNB 1）中的作用。我们确定了237个潜在的调节基因，基因产物的负或正作用被映射到抗病毒反应的不同步骤。在这些基因中，我们发现WNT家族的两个成员WNT 2B和WNT 9 B负调节IFNB 1反应。我们发现，SeV感染诱导WNT配体的分泌，β-catenin（CTNNB 1）的稳定，并在反馈机制中降低IFNB 1的表达。我们进一步证明，糖原合成酶激酶3（GSK 3）的抑制减少了抗病毒的先天性反应，在CTNNB 1依赖性的方式。研究结果表明，靶向这种新发现的经典样WNT/CTNNB 1信号通路的药物可能在治疗上有助于调节病毒复制或病毒诱导的炎症。
To identify new regulators of antiviral innate immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-β (IFNB1) promoter following Sendai virus (SeV) infection. We now report a novel link between WNT signaling pathway and the modulation of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-dependent innate immune responses. Here we show that secretion of WNT2B and WNT9B and stabilization of β-catenin (CTNNB1) upon virus infection negatively regulate expression of representative inducible genes IFNB1, IFIT1 and TNF in a CTNNB1-dependent effector mechanism. The antiviral response is drastically reduced by glycogen synthase kinase 3 (GSK3) inhibitors but restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of antiviral innate immunity by a canonical-like WNT/CTNNB1 signaling pathway. The study identifies novel avenues for broad-spectrum antiviral targets and preventing immune-mediated diseases upon viral infection. The innate immune system is the first line of defense for organisms that possess an adaptive immune system. It allows a rapid immune response upon viral infections, in addition to propagating an antiviral state in neighboring cells. In an attempt to identify new proteins that are involved in antiviral responses, we completed the first genome-wide RNA interference (RNAi) screen by individually silencing the expression of 15,000 human genes to assess their role in the induction of type I interferon-β (IFNB1) upon Sendai virus (SeV) infection. We identified 237 potential modulator genes for which negative or positive actions of gene products were mapped to the different steps of the antiviral responses. Among these genes, we find two members of the WNT family WNT2B and WNT9B that negatively regulate the IFNB1 response. We show that SeV infection induces the secretion of WNT ligands, stabilization of β-catenin (CTNNB1) and decreases expression of IFNB1 in a feedback mechanism. We further demonstrate that inhibition of glycogen synthase kinase 3 (GSK3) reduces the antiviral innate response in a CTNNB1-dependent manner. The findings suggest that drugs targeting this newly identified canonical-like WNT/CTNNB1 signaling pathway may be therapeutically useful to modulate viral replication or virus-induced inflammation.
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