SnapShot: pathways of antiviral innate immunity.
SnapShot: pathways of antiviral innate immunity.
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DOI：
10.1016/j.cell.2010.01.041
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发表时间：
2010-02-05
期刊：
影响因子：
64.5
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Sun L;Liu S;Chen ZJ
病毒性疾病仍然是一个具有挑战性的全球卫生问题。先天免疫是抵抗病毒感染的第一道防线。抗病毒先天免疫应答的标志是1型干扰素和炎性细胞因子的产生。这些分子不仅通过抑制病毒复制和组装快速遏制病毒感染，而且在激活适应性免疫系统以根除病毒方面发挥关键作用。最近的研究已经揭示了检测病毒感染的多种信号传导途径，其中几种途径检测病毒核酸的存在。细胞质途径许多病毒感染，特别是RNA病毒感染，都会导致病毒RNA在感染宿主细胞的胞质中传递和复制，因此，病毒核酸在感染宿主细胞的胞质中的传递和复制是病毒感染的主要途径。这些病毒RNA通常含有5′-三磷酸（5′-ppp）和由双链片段组成的泛肽样二级结构。这些特征被RIG-I样受体（RLR）家族的成员识别，所述RLR家族包括RIG-I、MDA 5和LGP 2（Fujita，2009; Yoneyama等人，2004年）。所有RLR在中间含有DEAD/H-box RNA解旋酶结构域。此外，RIG-I和LGP 2含有与5′-pppRNA结合的C-末端调节结构域（RD）。另一方面，MDA 5识别来自小核糖核酸病毒的长双链RNA（dsRNA）以及单链RNA（ssRNA）。RIG-I和MDA 5，而不是LGP 2，也含有两个N-末端CARD结构域，其与位于线粒体外膜中的衔接蛋白MAVS（也称为IPS-1、VISA或CARDIF）的CARD结构域相互作用。MAVS与STING（也称为MITA）相互作用，STING是线粒体和内质网（ER）中的跨膜蛋白。在ER膜上，STING与TRAP复合物结合，TRAP复合物可能参与募集蛋白激酶TBK 1和IKKε以磷酸化转录因子IRF 3。MAVS还募集泛素连接酶TRAF 3和TRAF 6，它们分别激活TBK 1和另一种激酶IKK。IKK磷酸化IκB（一种主转录因子NF-κB的抑制剂），导致IκB的泛素化及其随后的降解。然后NF-κB进入细胞核，开启过多的促炎基因。NF-κB还与IRF 3、IRF 7和其他转录因子结合以诱导IFN-β的产生。一些DNA病毒和细胞内细菌的感染也导致1型干扰素的有效诱导。由这些病原体引入的胞质DNA由不同的传感器检测。富含AT的DNA被RNA聚合酶III识别，RNA聚合酶III将DNA转录成5′-pppRNA，从而触发RIG-I途径。胞质DNA也可以通过RIG-I独立机制诱导干扰素，包括涉及其他DNA传感器如DAI和衔接蛋白如STING的机制。除了诱导1型干扰素的产生外，胞质DNA还可以激活炎性小体，其将IL-1β前体蛋白转化为成熟的细胞因子。在该途径中，胞质DNA被AIM 2识别，AIM 2与ASC和半胱天冬酶原-1形成复合物，导致半胱天冬酶-1活化（Schroder等人，2009年）。胞质RNA还可以通过RIG-I激活炎性小体，RIG-I接合ASC以激活半胱天冬酶-1。
Viral diseases remain a challenging global health issue. Innate immunity is the first line of defense against viral infection. A hallmark of antiviral innate immune responses is the production of type 1 interferons and inflammatory cytokines. These molecules not only rapidly contain viral infection by inhibiting viral replication and assembly but also play a crucial role in activating the adaptive immune system to eradicate the virus. Recent research has unveiled multiple signaling pathways that detect viral infection, with several pathways detecting the presence of viral nucleic acids. This SnapShot focuses on innate signaling pathways triggered by viral nucleic acids that are delivered to the cytosol and endosomes of mammalian host cells.Cytosolic Pathways Many viral infections, especially those of RNA viruses, result in the delivery and replication of viral RNA in the cytosol of infected host cells. These viral RNAs often contain 5′-triphosphate (5′-ppp) and panhandle-like secondary structures composed of double-stranded segments. These features are recognized by members of the RIG-I-like Receptor (RLR) family, which includes RIG-I, MDA5, and LGP2 (Fujita, 2009; Yoneyama et al., 2004). All RLRs contain a DEAD/H-box RNA helicase domain in the middle. In addition, RIG-I and LGP2 contain a C-terminal regulatory domain (RD) that binds to 5′-pppRNA. MDA5, on the other hand, recognizes long double-stranded RNAs (dsRNAs) as well as single-stranded RNAs (ssRNAs) derived from picornaviruses. RIG-I and MDA5, but not LGP2, also contain two N-terminal CARD domains that interact with the CARD domain of the adaptor protein MAVS (also known as IPS-1, VISA, or CARDIF), which resides in the mitochondrial outer membrane. MAVS interacts with STING (also known as MITA), a transmembrane protein in mitochondria and the endoplasmic reticulum (ER). On the ER membrane, STING associates with the TRAP complex, which may be involved in recruiting the protein kinases TBK1 and IKKε to phosphorylate the transcription factor IRF3. MAVS also recruits the ubiquitin ligases TRAF3 and TRAF6, which activate TBK1 and another kinase IKK, respectively. IKK phosphorylates IκB, an inhibitor of the master transcription factor NF-κB, leading to the ubiquitination of IκB and its subsequent degradation. NF-κB then enters the nucleus to turn on a plethora of proinflammatory genes. NF-κB also associates with IRF3, IRF7, and other transcription factors to induce production of IFN-β. Infection by some DNA viruses and intracellular bacteria also leads to potent induction of type 1 interferons. The cytosolic DNAs introduced by these pathogens are detected by distinct sensors. AT-rich DNA is recognized by RNA polymerase III, which transcribes the DNA into 5′-pppRNA that triggers the RIG-I pathway. Cytosolic DNA can also induce interferons through RIG-I-independent mechanisms, including those involving other DNA sensors such as DAI and adaptor proteins such as STING. In addition to inducing production of type 1 interferons, cytosolic DNA can activate the inflammasome, which converts the IL-1β precursor protein into the mature cytokine. In this pathway, cytosolic DNA is recognized by AIM2, which forms a complex with ASC and procaspase-1, resulting in caspase-1 activation (Schroder et al., 2009). Cytosolic RNA can also activate the inflammasome through RIG-I, which engages ASC to activate caspase-1.
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DOI：
10.1038/nri2337
发表时间：
2008-07
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Sun SC
通讯作者：
Sun SC
影响因子：
64.8
作者：
Kim, You-Me;Brinkmann, Melanie M.;Ploegh, Hidde L.
通讯作者：
Ploegh, Hidde L.
影响因子：
30.5
作者：
Tabeta, K;Hoebe, K;Beutler, B
通讯作者：
Beutler, B
影响因子：
30.5
作者：
Yoneyama, M;Kikuchi, M;Fujita, T
通讯作者：
Fujita, T