Toll-like Receptor(TLR) Signaling Bacteria Bacteria Yeast Zymosan TIRAP TIRAP TRIF MyD88 MyD88 FADD IRAK4 TRAF6 TRAF6 RIP1 IRAK1 IRAK4 TAB1/2 TRAF6 IRAK1/2 PI3K Rac1 Akt IKK Expression of Pro-inflammatory Cytokines Apoptosis Expression of Type I Interferon IκB IKKε ISRE Casp-8 Caspase Degradation Cascade TLR2 TLR1 TLR5 TLR5 dsRNA ssRNA CpG DNA NAP1 TLR4 CD14 BLP/LAM/PGN Flagellin LPS MD-2 TRIF TLR4 TRAF3 TAK1 TLR6 TLR2 CD14 ERK Bacteria Bacteria Cell Membrane Nuclear Membrane Nucleus IRF5 IRF7 IRF3 TBK1 TLR3 TANK TLR7 TLR8 TLR9 TLR3 TRAM TIRAP MyD88 MyD88 MyD88 MyD88 MKKs IKKs p38 JNK NF- B IRF7 IRF5 c-Jun IRF3 I B NF- B ISRE ISRE Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. TLRs play crucial roles in the innate immune system by recognizing various ligands of pathogen-associated molecular patterns (PAMPs, e.g. dsRNA) derived from various microbes or damage-associated molecular patterns (DAMPs) derived from damaged cell contents (not shown). TLRs localize to the cell surface or to intracellular compartments (e.g. endosome). Homo- or heterodimer formation initiates signaling to the two major downstream adaptor proteins, MyD88 and TRIF. TIRAP conducts the signal from TLR4 to MyD88, and TRAM mediates the signal from TLR4 to TRIF. TLR engagement induces formation of the Myddosome, which is based on MyD88 and also contains IRAK1 and IRAK4. IRAK1 activation induces TRAF6 activation following K63-linked polyubiquitination on TRAF6 itself and TAK1. TAK1 activation leads to the activation of IKK complex-NF-kB and MAPKs (e.g. ERK, JNK, p38). MAPK activation leads to AP1 (e.g. c-jun) activation. TLR engagement also induces TRIF activation following TRAF6 and TRAF3 recruitment. TRAF3 recruits TBK1 and IKKε for IRFs phosphorylation and expression of interferon-β. Abbreviations: dsRNA, double-stranded RNA; ssRNA, single-stranded RNA; BLP, Bacteria Lipoprotein; LAM, lipoarabinomannan; PGN, peptidoglycan; ISRE, Interferon-sensitive response
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Toll-like Receptor(TLR) Signaling
Bacteria
Bacteria
Yeast
Zymosan
TIRAP
TIRAP
TRIF
MyD88
MyD88
FADD
IRAK4
TRAF6
TRAF6
RIP1
IRAK1
IRAK4
TAB1/2
TRAF6 IRAK1/2
PI3K
Rac1
Akt
IKK
Expression of Pro-inflammatory CytokinesApoptosis Expression of Type I Interferon
IκB
IKKε
ISRE
Casp-8
Caspase
Degradation
Cascade
TL
R2
TL
R1
TL
R5
TL
R5
dsRNA
ssRNA
CpG DNA
NAP1
TL
R4
CD
14
BLP/LAM/PGN Flagellin LPS
MD-2
TRIF
TL
R4
TRAF3TAK1
TL
R6
TL
R2
CD
14
ERK
Bacteria Bacteria
Cell Membrane
Nuclear Membrane
Nucleus
IRF5 IRF7 IRF3
TBK1
TLR3
TANK
TLR7
TLR8
TLR9
TLR3
TRAMTIRAP
MyD88
MyD88
MyD88
MyD88
MKKsIKKs
p38JNK
NF-�B IRF7IRF5c-Jun IRF3
I�B�
NF-�B
ISRE ISRE
Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. TLRs play crucial
roles in the innate immune system by recognizing various ligands of pathogen-associated molecular patterns (PAMPs, e.g.
dsRNA) derived from various microbes or damage-associated molecular patterns (DAMPs) derived from damaged cell
contents (not shown). TLRs localize to the cell surface or to intracellular compartments (e.g. endosome). Homo- or
heterodimer formation initiates signaling to the two major downstream adaptor proteins, MyD88 and TRIF. TIRAP conducts
the signal from TLR4 to MyD88, and TRAM mediates the signal from TLR4 to TRIF. TLR engagement induces formation of
the Myddosome, which is based on MyD88 and also contains IRAK1 and IRAK4. IRAK1 activation induces TRAF6 activation
following K63-linked polyubiquitination on TRAF6 itself and TAK1. TAK1 activation leads to the activation of IKK
complex-NF-kB and MAPKs (e.g. ERK, JNK, p38). MAPK activation leads to AP1 (e.g. c-jun) activation. TLR engagement
also induces TRIF activation following TRAF6 and TRAF3 recruitment. TRAF3 recruits TBK1 and IKKε for IRFs
phosphorylation and expression of interferon-β. Abbreviations: dsRNA, double-stranded RNA; ssRNA, single-stranded