{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T02:56:43Z","timestamp":1787713003543,"version":"build-2784847793"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,1,9]]},"abstract":"<jats:p>RIG-I is an RNA helicase containing caspase activation and recruitment domains (CARDs). RNA binding and signaling by RIG-I are implicated in pathogen recognition and triggering of IFN-\u03b1\/\u03b2 immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes that control RIG-I signaling. RNA binding studies and analysis of cells lacking RIG-I, or the related MDA5 protein, demonstrated that RIG-I, but not MDA5, efficiently binds to secondary structured HCV RNA to confer induction of IFN-\u03b2 expression. We also found that LGP2, a helicase related to RIG-I and MDA5 but lacking CARDs and functioning as a negative regulator of host defense, binds HCV RNA. In resting cells, RIG-I is maintained as a monomer in an autoinhibited state, but during virus infection and RNA binding it undergoes a conformation shift that promotes self-association and CARD interactions with the IPS-1 adaptor protein to signal IFN regulatory factor 3- and NF-\u03baB-responsive genes. This reaction is governed by an internal repressor domain (RD) that controls RIG-I multimerization and IPS-1 interaction. Deletion of the RIG-I RD resulted in constitutive signaling to the IFN-\u03b2 promoter, whereas RD expression alone prevented signaling and increased cellular permissiveness to HCV. We identified an analogous RD within LGP2 that interacts in trans with RIG-I to ablate self-association and signaling. Thus, RIG-I is a cytoplasmic sensor of HCV and is governed by RD interactions that are shared with LGP2 as an on\/off switch controlling innate defenses. Modulation of RIG-I\/LGP2 interaction dynamics may have therapeutic implications for immune regulation.<\/jats:p>","DOI":"10.1073\/pnas.0606699104","type":"journal-article","created":{"date-parts":[[2006,12,26]],"date-time":"2006-12-26T20:13:52Z","timestamp":1167164032000},"page":"582-587","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":608,"title":["Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2"],"prefix":"10.1073","volume":"104","author":[{"given":"Takeshi","family":"Saito","sequence":"first","affiliation":[{"name":"Departments of *Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Hirai","sequence":"additional","affiliation":[{"name":"Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Ming","family":"Loo","sequence":"additional","affiliation":[{"name":"Departments of *Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Owen","sequence":"additional","affiliation":[{"name":"Departments of *Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia L.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Departments of *Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangita C.","family":"Sinha","sequence":"additional","affiliation":[{"name":"Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75235-9048;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuo","family":"Akira","sequence":"additional","affiliation":[{"name":"Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 560-0043, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Genetics and Molecular Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Michael","family":"Gale","sequence":"additional","affiliation":[{"name":"Departments of *Microbiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,1,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04946"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1087"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022637199"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.5.2851"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04734"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.5.2689-2699.2005"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1243"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2005.11.004"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2001.6661"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601523103"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1082604"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408707102"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050821"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.7640104"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(02)00298-1"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.24.13001-13014.2002"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1268"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132505"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1132998"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.21.14560"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.50.33489"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01325-06"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.8.5260"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.04.010"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0603082103"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510300137"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0606699104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T14:55:00Z","timestamp":1649775300000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0606699104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,1,9]]},"references-count":26,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2007,1,9]]}},"alternative-id":["10.1073\/pnas.0606699104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0606699104","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1059732.511649","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,1,9]]},"assertion":[{"value":"2006-08-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-01-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}