Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2
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-α/β immune defenses that impact cell permissiveness for hepatitis C virus (HCV). Here we evaluated the processes tha...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 2; pp. 582 - 587 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
09.01.2007
National Acad Sciences |
Subjects | |
Online Access | Get full text |
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Summary: | 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-α/β 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-β 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-κB-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-β 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved November 1, 2006 Author contributions: T.S., R.H., C.L.J., T.F., and M.G. designed research; T.S., R.H., Y.-M.L., D.O., C.L.J., S.C.S., T.F., and M.G. performed research; T.S., Y.-M.L., S.A., and M.G. contributed new reagents/analytic tools; T.S., D.O., C.L.J., S.C.S., T.F., and M.G. analyzed data; and T.S. and R.H. wrote the paper. |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0606699104 |