An Inheritable variant of the innate immune receptor melanoma differentiation-associated gene 5 promotes clearance of hepatitis C virus.
An Inheritable variant of the innate immune receptor melanoma differentiation-associated gene 5 promotes clearance of hepatitis C virus.
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先天免疫受体黑色素瘤分化相关基因 5 的可遗传变体可促进丙型肝炎病毒的清除。
DOI：
10.1002/hep.27439
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Modis,Yorgo
中科院分区：
文献类型：
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作者：
Modis,Yorgo
作为慢性肝病和癌症的主要原因，丙型肝炎病毒（HCV）是一种严重且持续的全球健康威胁。 1 Hoffmann 等人在最新一期《肝病学》上发表的文章中。确定了黑色素瘤分化相关基因 5 (mda5) 基因中不太常见的单核苷酸多态性 (SNP) 变异，该变异与丙型肝炎自发恢复率显着较高以及 HCV 患者慢性感染率较低相关。 2 携带 mda5 这种小等位基因的患者的 HCV 清除效率更高，是因为细胞响应双链 RNA (dsRNA) 而增加了细胞因子分泌。这表明 MDA5 响应细胞质 dsRNA 的信号传导活性（HCV 感染的标志）在 MDA5 的保护性变体中得到增强。这一新发现表明 MDA5 参与了 HCV 感染的自然过程。大多数包膜病毒要么将RNA基因组递送到宿主细胞的细胞质中，要么在病毒基因组的复制或转录过程中在细胞质中生成RNA。这些病毒的感染主要由一对重要的免疫传感器、视黄酸诱导基因 1 (RIG-I) 和 MDA5 检测。 3-5 RIGI 或 MDA5 与细胞质病毒 RNA 的结合会诱导传感器蛋白发生构象变化，从而指导大型寡聚信号平台的协同组装，从而导致信号接头、线粒体抗病毒信号蛋白（MAVS；干扰素 [IFN] 启动子刺激器 1 IPS-1）的募集和激活。 6-8 随后迅速发生的炎症反应最终导致核因子 kappa B 和 I 型 IFN 信号通路的激活。这种反应是抵御感染的第一道也是最重要的防线之一，负责激活适应性免疫系统。 9 因此，RIG-I 和 MDA5 作为炎症的主要调节因子发挥着关键作用。 HCV 是一种有包膜 RNA 病毒，已知由 RIG-I 样受体 (RLR) 信号通路感知和控制。事实上，Huh-7.5 细胞的 RIG-I 发生突变，使 RIG-I 信号失活，从而使它们更容易受到 HCV 复制的影响。 10, 11 然而，迄今为止，MDA5 尚未直接涉及 HCV 的抗病毒反应。值得注意的是，RIG-I 和 MDA5 的下游信号转导接头 MAVS 被 HCV 的非结构 3/4A 蛋白酶切割。 12, 13 事实上，MAVS（而不是 RLR 本身）是病毒因子抑制 RLR 信号传导的主要目标。 8 Hoffmann 等人的研究。提供了 MDA5 直接参与抗 HCV 信号传导的第一个证据。
As a leading cause of chronic liver disease and cancer, hepatitis C virus (HCV) is a serious and persistent global health threat. 1 In their article in the current issue of HEPATOLOGY, Hoffmann et al. identified the less frequent variant of a singlenucleotide polymorphism (SNP) in the melanoma differentiation-associated gene 5 (mda5) gene that is associated with a significantly higher rate of spontaneous recovery from hepatitis C, as well as a lower rate of chronic infection in HCV patients. 2 The more efficient clearance of HCV in patients harboring this minor allele of mda5 stems from increased cytokine secretion by cells in response to double-stranded RNA (dsRNA). This suggests that the signaling activity of MDA5 in response to cytoplasmic dsRNA, which is a hallmark of HCV infection, is enhanced in the protective variant of MDA5. This new finding implicates MDA5 in the natural course of HCV infection. Most enveloped viruses either deliver an RNA genome into the cytoplasm of the host cell or generate RNA in the cytoplasm during replication or transcription of the viral genome. Infection by these viruses is primarily detected by a pair of essential immune sensors, retinoic acid-inducible gene 1 (RIG-I) andMDA5. 3-5 Binding of cytoplasmic viral RNA by RIGI or MDA5 induces a conformational change in the sensor protein that directs the cooperative assembly of large oligomeric signaling platforms, leading to the recruitment and activation of the signaling adaptor, mitochondrial antiviral-signaling protein (MAVS; interferon [IFN] promoter stimulator 1 IPS-1). 6-8 The rapidly ensuing inflammatory response culminates in activation of the nuclear factor kappa B–and type I IFN-signaling pathways. This response is one of the first and most important lines of defense against infection and is responsible for the activation of the adaptive immune system. 9 Therefore, RIG-I and MDA5 play pivotal roles as master regulators of inflammation. HCV is an enveloped RNA virus known to be sensed and controlled by the RIG-I-like receptor (RLR)-signaling pathway. Indeed, Huh-7.5 cells have a mutation in RIG-I that inactivates RIG-I signaling that renders them much more susceptible to HCV replication. 10, 11 However, MDA5 had not, until now, been directly implicated in the antiviral response against HCV. Notably, the downstream signaling adaptor of both RIG-I and MDA5, MAVS, is cleaved by the nonstructural 3/4A protease of HCV. 12, 13 Indeed, MAVS—and not the RLRs themselves—is the primary target of viral factors for inhibiting RLR signaling. 8 The study by Hoffmann et al. provides the first evidence that MDA5 is directly involved in anti-HCV signaling.