LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses.
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.
Satoh
Takashi
T
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Kato
Hiroki
H
Kumagai
Yutaro
Y
Yoneyama
Mitsutoshi
M
Sato
Shintaro
S
Matsushita
Kazufumi
K
Tsujimura
Tohru
T
Fujita
Takashi
T
Akira
Shizuo
S
Takeuchi
Osamu
O
D000818:Animals; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology* / Q000378:metabolism; D004686:Encephalomyocarditis virus / Q000276:immunology*; D005260:Female; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020365:RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology*; D015398:Signal Transduction; D015996:Survival Rate
D012367:RNA, Viral; D016899:Interferon-beta; C547666:Dhx58 protein, mouse; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D020365:RNA Helicases