RESUMO
Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses. In this report, we identify retinoic acid inducible gene I (RIG-I), which encodes a DExD/H box RNA helicase that contains a caspase recruitment domain, as an essential regulator for dsRNA-induced signaling, as assessed by functional screening and assays. A helicase domain with intact ATPase activity was responsible for the dsRNA-mediated signaling. The caspase recruitment domain transmitted 'downstream' signals, resulting in the activation of transcription factors NF-kappaB and IRF-3. Subsequent gene activation by these factors induced antiviral functions, including type I interferon production. Thus, RIG-I is key in the detection and subsequent eradication of the replicating viral genomes.
Assuntos
Proteínas/metabolismo , RNA Helicases/metabolismo , RNA de Cadeia Dupla/fisiologia , Vírus/crescimento & desenvolvimento , Vírus/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Genes Reporter/genética , Humanos , Fator Regulador 3 de Interferon , Interferons/biossíntese , Interferons/genética , Interferons/imunologia , Camundongos , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Estrutura Terciária de Proteína , Proteínas/química , Proteínas/genética , RNA Helicases/química , RNA Helicases/genética , RNA de Cadeia Dupla/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Deleção de Sequência , Transdução de Sinais , Transativadores , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Infections of bacteria and viruses induce host defense reactions known as innate responses that include the production of cytokines and chemokines. The production of type I interferon (IFN) is known to be induced by viral double-stranded (ds) RNA or bacterial lipopolysaccharide (LPS). Although important functions for the transcription factors NF-kappaB and interferon regulatory factor-3 (IRF-3) are indicated, the molecular signals leading to the activation of IFN genes have yet to be elucidated. We provide several lines of evidence that LPS and dsRNA trigger distinct intracellular signals upstream. Notably, our investigation revealed a critical function for TIRAP/MAL, a signaling adapter for Toll-like receptor (TLR) 4, in LPS-induced but not dsRNA-induced activation of IRF-3. These results highlight cross-talk between TLR-mediated and virus/dsRNA-induced signals resulting in activation of the IFN system.
