Immunology Mounting a Response to Viral Infection

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Pathogen recognition receptors are important first responders to viral infection that bind to viral proteins or nucleic acids to trigger the immune response. RIG-1 is an RNA helicase with tandem caspase activation and recruitment domains (CARDs) that binds viral RNA and ultimately stimulates the genes induced by interferon regulator factor 3 (IRF-3) and nuclear factor B (NF-B). The CARDs of RIG-1 interact with the CARD of interferon (IFN)- promoter stimulator 1 (IPS-1), an adaptor that links RIG-1 to the signaling pathway that leads to gene activation. Saito et al. report that RIG-1 is maintained inactive as a result of the interaction of a C-terminal repressor domain (RD), and this autoinhibition is alleviated by binding to RNA with a secondary structure, including RNA from hepatitis C virus. A related helicase, LGP2, which lacks CARDs, also bound double-stranded RNA, including sequences from hepatitis C virus. Mutation analysis showed that RNA binding by RIG-1 required the helicase domain and the C terminus but did not require the CARDs. Trypsin digestion studies indicated that upon binding RNA, RIG-1 underwent a conformational change that displaced the C-terminal region. Downstream signaling, the interaction with IPS-1, and gene activation by RIG-1 in response to Sendai virus infection required both CARDs. However, a RIG-1 with a C-terminal deletion was constitutively activated, and the C-terminal domain served as a dominant-negative inhibiting RIG-1. In transfected cells, Sendai virus induced the formation of RIG-1 multimers, and this was blocked by coexpression of the C-terminal RD. The C-terminal domain of LGP2 is similar to that of RIG-1, and when transfected into cells expressing RIG-1, LGP2 prevented induction of gene expression in response to viral infection. Full-length LGP2 or the C-terminal RD region formed a complex with RIG-1 when the proteins were overexpressed. Expression of the RIG-1 RD in cells conferred increased permissiveness to viral infection with Sendai virus. Thus, the RD of RIG-1 keeps RIG-1 inactive until viral RNA is present; then a conformational change alleviates this repression, allowing RIG-1 to interact with IPS-1 and stimulate genes involved in the immune response. LGP2, through its RD, appears to act in trans to inhibit RIG-1. Thus, these two proteins appear to serve as modulators of the response--RIG-1 turns it on, and LGP2 turns it off.

T. Saito, R. Hirai, Y.-M. Loo, D. Owen, C. L. Johnson, S. C. Sinha, S. Akira, T. Fujita, M. Gale Jr., Regulation of innate antiviral defenses through a shared repressor domain in RIG-1 and LGP2. Proc. Natl. Acad. Sci. U.S.A. 104, 582-587 (2007). [Abstract] [Full Text]

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