The kinase complex responsible for IRF-3-mediated IFN-beta production in myeloid dendritic cells (mDC).
Type I interferons (IFN) IFN-alpha and -beta play a central role in the induction of antiviral immunity, which involves up-regulation or activation of a large number of IFN-inducible genes in host immune competent cells. Initial events in the antiviral response may occur in myeloid dendritic cells (mDCs), and the proteins expressed provoke early responses to cope with concomitant infection in the host. The participation of transcription factors IRF-3/7, AP1 and NF-kappaB in IFN-beta promoter activation in mDCs is well established. An initial trigger of this event is a viral dsRNA that is recognized by proteins with an RNA-binding motif. Toll-like receptor (TLR) 3 on membranes and RIG-Iin the cytoplasm are molecules with dsRNA-recognition ability. Our main aim in the present review is to describe how IRF-3 and/or NF-kappaB are activated through the initial recognition of dsRNA by these pattern-recognition receptors. By analogy to the trimolecular complex of IKKgamma, IKKalpha and IKKbeta, thus far, IRF-3-activated kinases have been reported to be kinase complexes with trimolecular assembly. Two kinases, TBK1 and IKKepsilon, are thought to be linked to regulatory subunit TANK or NAP1 with no kinase activity like IKKgamma. The TLR3 and RIG-I pathways converge upstream of IRF-3, possibly at NAP1, the regulatory subunit of IRF-3-activating kinase. Thus, a novel function of the regulatory subunit has emerged. These proteins are involved in the TLR3 and RIG-I pathways, and act as adapters bridging on the dsRNA-recognition unit and IRF-3-activating kinases in addition to their kinase-regulatory function. Here, we summarize the properties of regulatory subunits NAP1 and TANK, and the mode of activation of NF-kappaB and IRF-3 in conjunction with the unique properties of the TLR3 function.
Sasai
Miwa
M
Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Sapporo 060-8638, Japan.
Matsumoto
Misako
M
Seya
Tsukasa
T
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis*; D018448:Models, Immunological; D046912:Multiprotein Complexes / Q000378:metabolism; D022423:Myeloid Cells / Q000276:immunology*
D050838:Interferon Regulatory Factor-3; D046912:Multiprotein Complexes; D016899:Interferon-beta; D051550:I-kappa B Kinase