LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses

被引:505
作者
Satoh, Takashi [1 ]
Kato, Hiroki [1 ]
Kumagai, Yutaro [1 ]
Yoneyama, Mitsutoshi [2 ,3 ,4 ]
Sato, Shintaro [1 ]
Matsushita, Kazufumi [1 ]
Tsujimura, Tohru [5 ]
Fujita, Takashi [2 ,3 ]
Akira, Shizuo [1 ]
Takeuchi, Osamu [1 ]
机构
[1] Osaka Univ, Microbial Dis Res Inst, Host Def Lab, WPI Immunol Frontier Res Ctr, Suita, Osaka 5650871, Japan
[2] Kyoto Univ, Inst Virus Res, Dept Genet & Mol Biol, Kyoto 6068507, Japan
[3] Kyoto Univ, Grad Sch Biostudies, Mol Cell Biol Lab, Kyoto 6068507, Japan
[4] Japan Sci & Technol Agcy, PRESTO, Saitama, Japan
[5] Hyogo Coll Med, Dept Pathol, Nishinomiya, Hyogo 6638501, Japan
基金
美国国家卫生研究院;
关键词
innate immunity; type I interferon; virus infection; DOUBLE-STRANDED-RNA; INDUCIBLE GENE-I; INNATE IMMUNITY; HELICASE LGP2; RECOGNITION; MDA5; VIRUS; INDUCTION; FAMILY; DOMAIN;
D O I
10.1073/pnas.0912986107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1512 / 1517
页数:6
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