NV Proteins of Fish Novirhabdovirus Recruit Cellular PPM1Bb Protein Phosphatase and Antagonize RIG-I-Mediated IFN Induction.
NV Proteins of Fish Novirhabdovirus Recruit Cellular PPM1Bb Protein Phosphatase and Antagonize RIG-I-Mediated IFN Induction.
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DOI：
10.1038/srep44025
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发表时间：
2017-03-09
影响因子：
4.6
通讯作者：
Brémont M
中科院分区：
文献类型：
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作者：
Biacchesi S;Mérour E;Chevret D;Lamoureux A;Bernard J;Brémont M
非病毒粒子（NV）蛋白的表达是鱼类新哈比病毒、病毒性出血性败血症病毒（VHSV）和感染性造血坏死病毒（IHNV）体内发病的关键。然而，NV促进病毒复制的机制尚不清楚。我们开发了一种基于反向遗传学和相互作用学的方法，并确定了几种与nv相关的细胞伙伴，这些细胞通路是潜在的病毒靶标。在这些细胞伴侣中，我们发现NV蛋白特异性地与Mg2+/Mn2+依赖性蛋白磷酸酶1Bb （PPM1Bb）相互作用，并将其招募到线粒体附近，线粒体是对视黄酸诱导基因i - (RIG-I)介导的干扰素诱导途径很重要的亚细胞室。PPM1B蛋白属于丝氨酸/苏氨酸（Ser/Thr）蛋白磷酸酶PP2C家族，最近被证明通过去磷酸化Traf家族成员相关的NF-κB激活物（TANK）结合激酶1 （TBK1）负性调节宿主抗病毒反应。我们证明了NV蛋白和PPM1Bb在鱼细胞中抵抗RIG-I和tbk1依赖性干扰素（IFN）和IFN刺激的基因启动子诱导，从而建立抗病毒状态。此外，VHSV NV的表达强烈地降低了TBK1的磷酸化，从而使其活化。我们的发现为先前描述的病毒蛋白招募PPM1Bb蛋白磷酸酶来破坏先天免疫识别的机制提供了证据。
Non virion (NV) protein expression is critical for fish Novirhabdovirus, viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV), in vivo pathogenesis. However, the mechanism by which NV promotes the viral replication is still unclear. We developed an approach based on reverse genetics and interactomic and identified several NV-associated cellular partners underlying cellular pathways as potential viral targets. Among these cell partners, we showed that NV proteins specifically interact with a protein phosphatase, Mg2+/Mn2+-dependent, 1Bb (PPM1Bb) and recruit it in the close vicinity of mitochondria, a subcellular compartment important for retinoic acid-inducible gene-I- (RIG-I)-mediated interferon induction pathway. PPM1B proteins belong to the PP2C family of serine/threonine (Ser/Thr) protein phosphatase and have recently been shown to negatively regulate the host antiviral response via dephosphorylating Traf family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1). We demonstrated that NV proteins and PPM1Bb counteract RIG-I- and TBK1-dependent interferon (IFN) and IFN-stimulated gene promoter induction in fish cells and, hence, the establishment of an antiviral state. Furthermore, the expression of VHSV NV strongly reduced TBK1 phosphorylation and thus its activation. Our findings provide evidence for a previously undescribed mechanism by which a viral protein recruits PPM1Bb protein phosphatase to subvert innate immune recognition.