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-2.1685 -4.7554 -2.8574 -2.6168 -2.7559 l -20.0457 -7.9331 l -7.1327 0.0097 c 0.382 3.6124 1.4467 3.4357 -2.5782 5.3173 c -3.0417 2.2249 -4.2219 3.5825 -3.4632 1.6055 l -13.8362 16.3716 l -2.1949 6.7007 c 3.5976 0.7577 3.7566 -0.2969 4.3251 4.0641 c 1.2033 3.5437 2.1462 5.0715 0.4764 3.7482 l 11.4946 18.0513 l 5.7764 4.1315 c 1.8416 -3.1441 0.875 -3.6192 5.2514 -2.8055 c 3.7854 -0.035 5.5484 -0.4482 3.7577 0.7109 l 20.9402 -5.2151 l 5.7648 -4.1472 z" /> </svg> PMID: 17904888,14971051 TLR9 recognises dsDNA, often in the form of unmethylated CpG deoxyoligonucleotides PMID: 17904888,12900525 The downstream signalling proteins required for TLR9 mediated IFN-a gene include the adaptor MyD88, as DCs from MyD88 knockout mice fail to produce IFN-a PMID: 17904888,12900525 Further studies have demonstrated that in pDCs and HEK293 cells, TLR9 ligation causes the adaptor MyD88 to interact with the transcription factor IRF-7 and induce IFN-a gene expression. indirect PMID: 17904888,12900525 Further studies have demonstrated that in pDCs and HEK293 cells, TLR9 ligation causes the adaptor MyD88 to interact with the transcription factor IRF-7 and induce IFN-a gene expression. PMID: 17904888 This process involves a kinase complex containing TRAF6 and the IL-1 receptor associated kinase (IRAK). PMID: 17904888,15767370 In the different cell types, different family members of IRAK appear to be important, in pDCs, IRAK-1 was required however in HEK cells IRAK-4 was responsible PMID: 17904888,14530357 The TLR7 ligand imiquimod induces IFN-a in pDCs and monocytes PMID: 17904888 TLR7 ligation involves a signalling pathway consisting of MyD88, TRAF6 and IRAK-1, and this complex leads to IRF-5 and IRF-7 activation in HEK293 cells. indirect PMID: 17904888 TLR7 ligation involves a signalling pathway consisting of MyD88, TRAF6 and IRAK-1, and this complex leads to IRF-5 and IRF-7 activation in HEK293 cells. indirect PMID: 17904888 TLR7 ligation involves a signalling pathway consisting of MyD88, TRAF6 and IRAK-1, and this complex leads to IRF-5 and IRF-7 activation in HEK293 cells. PMID: 17904888,17038589 RIG-I recognises dsRNA and also is thought to associate with 50-triphosphorylated ssRNA derived from virally infected cells PMID: 17904888,17038589 RIG-I recognises dsRNA and also is thought to associate with 50-triphosphorylated ssRNA derived from virally infected cells PMID: 17904888,16127453 MDA5 has a helicase/CARD structure similar to that of RIG-I, and like RIG-I the helicase domain of MDA5 binds to viral dsRNA and its CARD domain can bind to the CARD-containing region of CARDIF/IPS PMID: 17904888,16127453 MDA5 has a helicase/CARD structure similar to that of RIG-I, and like RIG-I the helicase domain of MDA5 binds to viral dsRNA and its CARD domain can bind to the CARD-containing region of CARDIF/IPS PMID: 17904888 PKR homodimers are constitutively expressed in the cytoplasm, and activated by dsRNA ligation. indirect PMID: 17904888,7912826 NF-kB is a target of PKR, activated through phosphorylation of the inhibitor of NF-kB, IkB [35], or activation of the kinase phosphorylating IkB, IKK-a/ b PMID: 17904888,15502848 An initial study by Sarkar, in HEK293 cells revealed that TLR3 phosphorylation at conserved tyrosine residues within the intracellular domain recruits both TBK1 and PI3K. PMID: 17904888,15502848 An initial study by Sarkar, in HEK293 cells revealed that TLR3 phosphorylation at conserved tyrosine residues within the intracellular domain recruits both TBK1 and PI3K. indirect PMID: 17904888 JNK2 also activates c-Jun, half of the heterodimeric ATF-2/c-Jun transcription factor required for IFN-b expression indirect PMID: 17904888 JNK2 also activates c-Jun, half of the heterodimeric ATF-2/c-Jun transcription factor required for IFN-b expression indirect PMID: 17904888 The upstream activator or dsRNA recognition molecule that activates JNK2 in response to viral infection is currently unknown, however over-expression of the RIG-I adaptor CARDIF/ MAVS/VISA/IPS has been reported to activate JNK PMID: 17904888,16127453 Subsequent biochemical analysis identified RIG-I as an RNA helicase with a self-inhibiting conformation; unwinding of viral dsRNA in the presence of ATP allows the CARD signalling domains access to a CARD containing intermediate, identified by four groups as CARDIF, VISA, MAVS and IPS-1 PMID: 17904888,16585524 NS3or4A was observed to specifically cleave the helicase adaptor IPS-1, causing a loss of RIG-I and IPS-I interaction PMID: 17904888 This complex then makes contact with a kinase complex, which includes TANK, TANK binding kinase 1 (TBK1) and IKK-i/epsilon. PMID: 17904888,11607032 TLR3 was first identified in 2001 as an extracellular receptor for dsRNA in both human and murine cells PMID: 17904888 Further studies identified an important adaptor protein under the control of TLR3, termed TIR domain-containing adapter inducing IFN-b (TRIF) PMID: 17904888,15064760 The dual role of TRIF in both IFN-b gene expression and NF-kB activation can be further explained by the identification of kinase receptor interacting protein (RIP)-1 indirect PMID: 17904888 Hence RIP-1 mediates the NF-kB activating arm of TRIF mediated TLR3 function. PMID: 17904888 TLR3 ligation can activate IRF-3 via TRIF, and involves the kinases TBK1 and IKK-i or epsilon. indirect PMID: 17904888,12692549,16127453,16177806,14703513 ,16153868 Both the TLR3 associated adapter TRIF, and RIG-I adaptor CARDIF , have been immunoprecipitated with IKK-i/epsilon or TBK1, and these kinases have been shown to directly phosphorylate IRF-3 at Ser386, leading to its dimerisation PMID: 17904888,12692549,16127453,16177806,14703513 ,16153868 Both the TLR3 associated adapter TRIF, and RIG-I adaptor CARDIF , have been immunoprecipitated with IKK-i/epsilon or TBK1, and these kinases have been shown to directly phosphorylate IRF-3 at Ser386, leading to its dimerisation PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. indirect PMID: 17904888 Lung fibroblasts, and macrophages from TRIF deficient mice also had impaired IRF-3 phosphorylation after polyIC ligation suggesting TRIF induces IFN-b via the transcription factor IRF-3. indirect PMID: 17904888 Lung fibroblasts, and macrophages from TRIF deficient mice also had impaired IRF-3 phosphorylation after polyIC ligation suggesting TRIF induces IFN-b via the transcription factor IRF-3. indirect PMID: 17904888 RNA helicases RIG-I and MDA recognise intracellular viral dsRNA or ssRNA and activate NF-kB via IKK-b, or IRF-3 via TBK1, IKK-ior epsilon. PMID: 17904888 This complex then makes contact with a kinase complex, which includes TANK, TANK binding kinase 1 (TBK1) and IKK-i/epsilon. indirect PMID: 17904888 RNA helicases RIG-I and MDA recognise intracellular viral dsRNA or ssRNA and activate NF-kB via IKK-b, or IRF-3 via TBK1, IKK-ior epsilon. indirect PMID: 17904888 RNA helicases RIG-I and MDA recognise intracellular viral dsRNA or ssRNA and activate NF-kB via IKK-b, or IRF-3 via TBK1, IKK-ior epsilon. indirect PMID: 17904888 RNA helicases RIG-I and MDA recognise intracellular viral dsRNA or ssRNA and activate NF-kB via IKK-b, or IRF-3 via TBK1, IKK-ior epsilon. indirect PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. indirect PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. indirect PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. PMID: 17904888 Importantly, ISG56 expression could be inhibited by wortmannin and LY294002, potent inhibitors of PI3K, and IRF-3 association with CBP and the ISG56 promoter was inhibited, but nuclear translocation of IRF-3 was not inhibited. PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56. PMID: 17904888 Subsequent experiments showed that TLR3 mediated signalling to IRF-3 requires both TBK1 and PI3K for full phosphorylation of IRF-3 at Ser396, possibly via the PI3K target Akt, and hence formation of IRF-3 dimers and full induction of IRF responsive genes, such as ISG56.