PMID: 17904888,14971051 TLR9 recognises dsDNA, often in the form of unmethylated CpG deoxyoligonucleotides

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.

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.

PMID: 17904888 JNK2 also activates c-Jun, half of the heterodimeric ATF-2/c-Jun transcription factor required for IFN-b expression

PMID: 17904888 JNK2 also activates c-Jun, half of the heterodimeric ATF-2/c-Jun transcription factor required for IFN-b expression

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: 17904888,12900525 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: 17904888,16127453 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

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.

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.

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 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.

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.

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.

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 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 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 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: 17904888,12900525 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