LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses
LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses
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DOI：
10.1073/pnas.0912986107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
--
作者：
Satoh, Takashi;Kato, Hiroki;Takeuchi, Osamu
RNA病毒感染被视黄酸诱导基因（RIG）-I样受体（RLR）、RIG-1和细胞质中的黑色素瘤分化相关基因5（MDA 5）识别。TLR由N-末端半胱天冬酶募集结构域（CARD）和DExD/H-box解旋酶结构域组成。RLR家族的第三个成员LGP 2缺乏任何CARD，最初被鉴定为RLR信号传导的负调节因子。在本研究中，我们产生了缺乏LGP 2的小鼠，并发现LGP 2是RIG-I和MDA 5介导的抗病毒反应所必需的。特别是，LGP 2是必不可少的I型干扰素生产响应小RNA病毒科感染。来自RIG-I和MDA 5的CARD在Lgp 2（-/-）成纤维细胞中的过表达激活IFN-β启动子，表明LGP 2在RIG-I和MDA 5的上游起作用。我们进一步研究了LGP 2解旋酶结构域的作用，通过产生小鼠携带的点突变的赖氨酸-30到丙氨酸（Lgp 2（K30 A/K30 A）），废除LGP 2 ATP酶活性。Lgp 2（K30 A/K30 A）树突状细胞在响应各种RNA病毒时表现出与Lgp 2（-/-）细胞相似的IFN-β产生受损的程度。Lgp 2（-/-）和Lgp 2（K30 A/K30 A）小鼠对脑心肌炎病毒感染高度易感。然而，LGP 2及其ATP酶活性对于MDA 5和RIG-1的合成RNA配体的应答是不稳定的。综上所述，本数据表明LGP 2通过其ATP酶结构域促进RIG-I和MDA 5对病毒RNA的识别。
RNA virus infection is recognized by retinoic acid-inducible gene (RIG)-I- like receptors (RLRs), RIG-I, and melanoma differentiation-associated gene 5 (MDA5) in the cytoplasm. RLRs are comprised of N-terminal caspase-recruitment domains (CARDs) and a DExD/H-box helicase domain. The third member of the RLR family, LGP2, lacks any CARDs and was originally identified as a negative regulator of RLR signaling. In the present study, we generated mice lacking LGP2 and found that LGP2 was required for RIG-I- and MDA5-mediated antiviral responses. In particular, LGP2 was essential for type I IFN production in response to picornaviridae infection. Overexpression of the CARDs from RIG-I and MDA5 in Lgp2(-/-) fibroblasts activated the IFN-beta promoter, suggesting that LGP2 acts upstream of RIG-I and MDA5. We further examined the role of the LGP2 helicase domain by generating mice harboring a point mutation of Lys-30 to Ala (Lgp2(K30A/K30A)) that abrogated the LGP2 ATPase activity. Lgp2(K30A/K30A) dendritic cells showed impaired IFN-beta productions in response to various RNA viruses to extents similar to those of Lgp2(-/-) cells. Lgp2(-/-) and Lgp2(K30A/K30A) mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands for MDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.