2010.01.09

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

Takashi Satoh, Hiroki Kato, Yutaro Kumagai, Mitsutoshi Yoneyama, Shintaro Sato, Kazufumi Matsushita, Tohru Tsujimura, Takashi Fujita, Shizuo Akira and Osamu Takeuchi

PNAS

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-β 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 (Lgp2K30A/K30A) that abrogated the LGP2 ATPase activity. Lgp2K30A/K30A dendritic cells showed impaired IFN-β productions in response to various RNA viruses to extents similar to those of Lgp2−/− cells. Lgp2−/− and Lgp2K30A/K30A mice were highly susceptible to encephalomyocarditis virus infection. Nevertheless, LGP2 and its ATPase activity were dispensable for the responses to synthetic RNA ligands forMDA5 and RIG-I. Taken together, the present data suggest that LGP2 facilitates viral RNA recognition by RIG-I and MDA5 through its ATPase domain.


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