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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.