An accessory to the 'Trinity': SR-As are essential pathogen sensors of extracellular dsRNA, mediating entry and leading to subsequent type I IFN responses.
An accessory to the 'Trinity': SR-As are essential pathogen sensors of extracellular dsRNA, mediating entry and leading to subsequent type I IFN responses.
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DOI：
10.1371/journal.ppat.1000829
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发表时间：
2010-03-26
期刊：
影响因子：
6.7
通讯作者：
Mossman KL
中科院分区：
文献类型：
--
作者：
DeWitte-Orr SJ;Collins SE;Bauer CM;Bowdish DM;Mossman KL
细胞外RNA越来越被认为是一种信号分子。病毒衍生的双链（ds）RNA在病毒诱导的细胞裂解过程中释放到细胞外空间，作为经典I型干扰素（IFN）反应的强大诱导剂；然而，介导这种反应的受体尚未被确定。A类清道夫受体（SR-As）由于其细胞表面表达和结合核酸的能力而成为可能的候选者。在这项研究中，我们研究了SR-As在成纤维细胞（IFNβ的主要产生者）中介导细胞外dsRNA诱导的I型IFN反应中的可能作用。成纤维细胞被发现表达功能性SR-A，甚至被认为是巨噬细胞特异性的SR-A。SR-A特异性竞争配体显著阻断细胞外dsRNA结合、进入和随后的干扰素刺激基因（ISG）诱导。使用RNAi系统地研究了候选SR-As，当所有候选SR-As被一致敲除时，观察到对反应的最显著抑制。与WT对照组相比，在SR-AI/II-/-小鼠体内观察到部分抑制dsRNA诱导的抗病毒反应。在小鼠和人成纤维细胞中观察到SR-As介导细胞外dsRNA进入和随后诱导的抗病毒反应的作用。sr - a似乎起着“载体”的作用，促进dsRNA进入并递送到已建立的dsRNA传感受体，特别是TLR3、RIGI和MDA-5。识别SR-As作为细胞的看门人，介导先天抗病毒反应，代表了该受体家族的新功能，并提供了细胞如何识别与溶性病毒感染相关的危险信号的见解。此外，能够识别细胞外RNA的细胞表面受体的意义可能超越病毒免疫，介导其他重要的先天免疫功能。几乎所有的病毒在其复制周期中都会产生dsRNA。这种分子通常在健康的宿主细胞中找不到，因此起着标志的作用，提醒宿主注意病毒感染。在病毒感染期间，细胞可因裂解而死亡，细胞内的dsRNA随后被释放到细胞外空间。这种dsRNA在细胞外环境中是稳定的，并且能够作为信号分子发挥作用，被邻近细胞检测到。这是实验观察到的，因为细胞外dsRNA多年来一直用于触发宿主抗病毒反应。也有研究表明，胞外dsRNA在病毒感染患者的病理症状中起作用。我们的数据表明，A类清道夫受体（SR-As）作为dsRNA的细胞表面受体发挥作用。SR-As结合细胞外的病毒dsRNA并介导其进入细胞，在细胞内将dsRNA传递给其他已知的细胞内dsRNA传感器，激活细胞内抗病毒反应。这些发现揭示了宿主如何检测和应对病毒感染。
Extracellular RNA is becoming increasingly recognized as a signaling molecule. Virally derived double stranded (ds)RNA released into the extracellular space during virus induced cell lysis acts as a powerful inducer of classical type I interferon (IFN) responses; however, the receptor that mediates this response has not been identified. Class A scavenger receptors (SR-As) are likely candidates due to their cell surface expression and ability to bind nucleic acids. In this study, we investigated a possible role for SR-As in mediating type I IFN responses induced by extracellular dsRNA in fibroblasts, a predominant producer of IFNβ. Fibroblasts were found to express functional SR-As, even SR-A species thought to be macrophage specific. SR-A specific competitive ligands significantly blocked extracellular dsRNA binding, entry and subsequent interferon stimulated gene (ISG) induction. Candidate SR-As were systematically investigated using RNAi and the most dramatic inhibition in responses was observed when all candidate SR-As were knocked down in unison. Partial inhibition of dsRNA induced antiviral responses was observed in vivo in SR-AI/II-/- mice compared with WT controls. The role of SR-As in mediating extracellular dsRNA entry and subsequent induced antiviral responses was observed in both murine and human fibroblasts. SR-As appear to function as ‘carriers’, facilitating dsRNA entry and delivery to the established dsRNA sensing receptors, specifically TLR3, RIGI and MDA-5. Identifying SR-As as gatekeepers of the cell, mediating innate antiviral responses, represents a novel function for this receptor family and provides insight into how cells recognize danger signals associated with lytic virus infections. Furthermore, the implications of a cell surface receptor capable of recognizing extracellular RNA may exceed beyond viral immunity to mediating other important innate immune functions. Nearly all viruses produce dsRNA during their replication cycle. This molecule is not normally found in a healthy host cell and thus functions as a flag, alerting the host to a viral infection. Cells can die by lysis during virus infections, and the intracellular dsRNA is then released into the extracellular space. This dsRNA is stable in the extracellular milieu, and is able to function as a signaling molecule, detected by neighboring cells. This has been observed experimentally, as extracellular dsRNA has been used for years to trigger host antiviral responses. It has also been suggested that extracellular dsRNA plays a role in causing pathological symptoms in virus infected patients. Our data suggests that class A scavenger receptors (SR-As) function as cell surface receptors for dsRNA. SR-As bind extracellular, viral dsRNA and mediate its entry into the cell, where it delivers the dsRNA to other known intracellular dsRNA sensors, activating intracellular antiviral responses. These findings shed new light on how the host detects and responds to virus infection.
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