Viral infections activate types I and III interferon genes through a common mechanism.
Viral infections trigger innate immune responses, including the production of type I interferons (IFN-alpha and -beta) and other proinflammatory cytokines. Novel antiviral cytokines IFN-lambda1, IFN-lambda2, and IFN-lambda3 are classified as type III IFNs and have evolved independently of type I IFNs. Type III IFN genes are regulated at the level of transcription and induced by viral infection. Although the regulatory mechanism of type I IFNs is well elucidated, the expression mechanism of IFN-lambdas is not well understood. Here, we analyzed the mechanism by which IFN-lambda gene expression is induced by viral infections. Loss- and gain-of-function experiments revealed the involvement of RIG-I (retinoic acid-inducible gene I), IPS-1, TBK1, and interferon regulatory factor-3, key regulators of the virus-induced activation of type I IFN genes. Consistent with this, a search for the cis-regulatory element of the human ifnlambda1 revealed a cluster of interferon regulatory factor-binding sites and a NF-kappaB-binding site. Functional analysis demonstrated that all of these sites are essential for gene activation by the virus. These results strongly suggest that types I and III IFN genes are regulated by a common mechanism.
Onoguchi
Kazuhide
K
Laboratory of Molecular Genetics, Institute for Virus Research and Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.
Yoneyama
Mitsutoshi
M
Takemura
Azumi
A
Akira
Shizuo
S
Taniguchi
Tadatsugu
T
Namiki
Hideo
H
Fujita
Takashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D007370:Interferon Type I / Q000235:genetics*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D024363:Transcription Initiation Site; D015533:Transcriptional Activation; D014777:Virus Diseases / Q000276:immunology*; D000095022:Interferon Lambda
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D007372:Interferons; D007378:Interleukins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C494232:IRF3 protein, human; C505371:MAVS protein, human; C403191:TBK1 protein, human; C452820:RIGI protein, human