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Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity

机译:丙型肝炎病毒蛋白酶NS3 / 4A从线粒体中裂解线粒体抗病毒信号蛋白逃避先天免疫

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摘要

Hepatitis C virus (HCV) is a global epidemic manifested mainly by chronic infection. One strategy that HCV employs to establish chronic infection is to use the viral Ser protease NS3/4A to cleave some unknown cellular targets involved in innate immunity. Here we show that the target of NS3/4A is the mitochondrial antiviral signaling protein, MAVS, that activates NF-κB and IFN regulatory factor 3 to induce type-I interferons. NS3/4A cleaves MAVS at Cys-508, resulting in the dislocation of the N-terminal fragment of MAVS from the mitochondria. Remarkably, a point mutation of MAVS at Cys-508 renders MAVS resistant to cleavage by NS3/4A, thus maintaining the ability of MAVS to induce interferons in HCV replicon cells. NS3/4A binds to and colocalizes with MAVS in the mitochondrial membrane, and it can cleave MAVS directly in vitro. These results provide an example of host–pathogen interaction in which the virus evades innate immunity by dislodging a pivotal antiviral protein from the mitochondria and suggest that blocking the cleavage of MAVS by NS3/4A may be applied to the prevention and treatment of HCV.
机译:丙型肝炎病毒(HCV)是一种全球流行病,主要表现为慢性感染。 HCV用于建立慢性感染的一种策略是使用病毒Ser蛋白酶NS3 / 4A裂解与先天免疫有关的某些未知细胞靶标。在这里,我们显示NS3 / 4A的靶标是线粒体抗病毒信号蛋白MAVS,它激活NF-κB和IFN调节因子3诱导I型干扰素。 NS3 / 4A在Cys-508处裂解MAVS,导致MAVS的N端片段从线粒体脱位。值得注意的是,Cys-508上MAVS的点突变使MAVS抵抗被NS3 / 4A切割,从而保持了MAVS诱导HCV复制子细胞中干扰素的能力。 NS3 / 4A与线粒体膜中的MAVS结合并共定位,并且可以在体外直接裂解MAVS。这些结果提供了一个宿主-病原体相互作用的例子,其中病毒通过从线粒体中清除关键的抗病毒蛋白而逃避了先天免疫力,并表明NS3 / 4A阻断MAVS的裂解可用于预防和治疗HCV。

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