期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 4, 页码 1512-1517出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0912986107
关键词
innate immunity; type I interferon; virus infection
资金
- Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare in Japan
- Global Center of Excellence Program of Japan
- National Institutes of Health [P01 AI070167]
- Grants-in-Aid for Scientific Research [20112009] Funding Source: KAKEN
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.
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