Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating toll-like receptor 3 recognition of viral RNAs produced in neighboring cells.
Class A scavenger receptor 1 (MSR1) restricts hepatitis C virus replication by mediating toll-like receptor 3 recognition of viral RNAs produced in neighboring cells.
复制标题
A类清除受体1（MSR1）通过介导类似Toll样受体3识别相邻细胞中产生的病毒RNA的识别来限制丙型肝炎病毒复制。
DOI：
10.1371/journal.ppat.1003345
复制
发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Lemon SM
中科院分区：
文献类型：
--
作者：
Dansako H;Yamane D;Welsch C;McGivern DR;Hu F;Kato N;Lemon SM
丙型肝炎病毒（HCV）的持续感染可导致危及生命的肝脏疾病，包括肝硬化和癌症，并对人类健康造成重大负担。因此，了解病毒如何能够在大多数感染者中持续存在是一个重要目标。虽然HCV已经进化出多种机制来破坏和阻断参与干扰素（IFN）应答诱导的细胞信号传导途径，但IFN刺激基因（ISG）表达通常在HCV感染的肝脏中突出。在这里，我们表明，Toll样受体3（TLR 3）在未感染的肝细胞内表达的是能够感应相邻细胞的感染，启动局部抗病毒反应，部分限制HCV复制。我们证明，这是依赖于A类清道夫受体1型（MSR 1）的表达。MSR 1结合细胞外dsRNA，介导其内吞作用并转运到内体，在那里它被TLR 3接合，从而在感染和未感染的细胞中触发IFN应答。RNAi介导的MSR 1表达敲低阻断了感染肝细胞培养物中HCV的TLR 3感应，导致细胞对病毒感染的容许性增加。Myc-MSR 1的外源性表达恢复了MSR 1耗尽细胞中的TLR 3信号传导，随后诱导了抗病毒状态。MSR 1的胶原超家族结构域的羧基末端内的一系列保守碱性残基是dsRNA的结合和转运所需的，并且可能促进dsRNA在内体中TLR 3表达位点的酸化依赖性释放。我们的研究结果揭示MSR 1是TLR 3介导的模式识别受体反应的关键组成部分，在感染和未感染的肝细胞中发挥抗病毒状态，从而限制HCV蛋白破坏感染细胞中IFN信号传导的影响，并限制HCV在肝脏内的传播。丙型肝炎病毒（HCV）持续感染是导致人类肝硬化和肝癌的重要原因。虽然病毒干扰素（IFN）信号通路的破坏可能有助于HCV的持续存在，但IFN刺激基因（ISG）的表达通常在感染的肝脏中很突出。我们在这里表明，这是由于，至少部分是由于Toll样受体3感应的HCV介导的A类清道夫受体1型（MSR 1）依赖性的内吞作用和细胞外病毒双链RNA（dsRNA）的运输，使其被从事的TLR 3在晚期内体。在未感染细胞内表达的TLR 3能够在依赖于MSR 1的dsRNA清除活性的过程中感测邻近感染细胞中的HCV感染，导致诱导局部功能性抗病毒应答。这有助于ISG的表达，代表慢性感染的肝脏，因为它发生在不表达破坏IFN信号传导的HCV蛋白的细胞内。因此，TLR 3信号限制了病毒在肝脏内的传播，这可能解释了为什么只有一小部分肝细胞在体内感染HCV。
Persistent infections with hepatitis C virus (HCV) may result in life-threatening liver disease, including cirrhosis and cancer, and impose an important burden on human health. Understanding how the virus is capable of achieving persistence in the majority of those infected is thus an important goal. Although HCV has evolved multiple mechanisms to disrupt and block cellular signaling pathways involved in the induction of interferon (IFN) responses, IFN-stimulated gene (ISG) expression is typically prominent in the HCV-infected liver. Here, we show that Toll-like receptor 3 (TLR3) expressed within uninfected hepatocytes is capable of sensing infection in adjacent cells, initiating a local antiviral response that partially restricts HCV replication. We demonstrate that this is dependent upon the expression of class A scavenger receptor type 1 (MSR1). MSR1 binds extracellular dsRNA, mediating its endocytosis and transport toward the endosome where it is engaged by TLR3, thereby triggering IFN responses in both infected and uninfected cells. RNAi-mediated knockdown of MSR1 expression blocks TLR3 sensing of HCV in infected hepatocyte cultures, leading to increased cellular permissiveness to virus infection. Exogenous expression of Myc-MSR1 restores TLR3 signaling in MSR1-depleted cells with subsequent induction of an antiviral state. A series of conserved basic residues within the carboxy-terminus of the collagen superfamily domain of MSR1 are required for binding and transport of dsRNA, and likely facilitate acidification-dependent release of dsRNA at the site of TLR3 expression in the endosome. Our findings reveal MSR1 to be a critical component of a TLR3-mediated pattern recognition receptor response that exerts an antiviral state in both infected and uninfected hepatocytes, thereby limiting the impact of HCV proteins that disrupt IFN signaling in infected cells and restricting the spread of HCV within the liver. Persistent hepatitis C virus (HCV) infection is an important cause of fatal cirrhosis and liver cancer in humans. While viral disruption of interferon (IFN) signaling pathways may contribute to the persistence of HCV, IFN-stimulated gene (ISG) expression is often prominent within the infected liver. We show here that this is due, at least in part, to Toll-like receptor 3 sensing of HCV mediated by class A scavenger receptor type 1 (MSR1)-dependent endocytosis and transport of extracellular viral double-stranded RNA (dsRNA) allowing it to be engaged by TLR3 in the late endosome. TLR3 expressed within uninfected cells is capable of sensing HCV infection in neighboring infected cells in a process that is dependent upon the dsRNA-scavenging activity of MSR1, resulting in the induction of a localized functional antiviral response. This contributes to the ISG expression that typifies the chronically-infected liver, as it occurs within cells that do not express HCV proteins that disrupt IFN signaling. TLR3 signaling thus limits the spread of virus within the liver, potentially explaining why only a small fraction of hepatocytes are infected with HCV in vivo.
登录
查看更多内容
影响因子：
6.7
作者：
DeWitte-Orr SJ;Collins SE;Bauer CM;Bowdish DM;Mossman KL
通讯作者：
Mossman KL
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
5.4
作者：
Blight, KJ;McKeating, JA;Rice, CM
通讯作者：
Rice, CM
DOI：
10.1073/pnas.0710779105
发表时间：
2008-01-08
影响因子：
11.1
作者：
Leonard, Joshua N.;Ghirlando, Rodolfo;Segal, David M.
通讯作者：
Segal, David M.
DOI：
10.1073/pnas.87.22.8810
发表时间：
1990-11-01
影响因子：
11.1
作者：
FREEMAN, M;ASHKENAS, J;KRIEGER, M
通讯作者：
KRIEGER, M