Toll-like receptor signaling (WP88)

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB and Mitogen-activated protein kinase. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKK-β. On binding, TAK1 phosphorylates IKK-β, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription and consequent induction of inflammatory cytokines. Both TLR3 and TLR4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TLR3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIPK1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Interferon type I. Meanwhile, activation of RIPK1 causes the polyubiquitination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway. Source: Wikipedia (http://en.wikipedia.org/wiki/Toll-like_receptor#Signaling)
last edited

Authors

Pietergoossens, MaintBot, Thomas, AlexanderPico, Ddigles, Khanspers, and Eweitz

Cited In

Organism

Mus musculus

Communities

Annotations

Pathway Ontology: Toll-like receptor signaling pathway

Participants

Label Type Compact Identifier
Pkr GeneProduct ncbigene:19106
IKBa GeneProduct ncbigene:17121
TRAM GeneProduct ncbigene:225471
Traf3 GeneProduct ncbigene:22031
Traf6 GeneProduct ncbigene:22034
Caspase-3 GeneProduct ncbigene:12367
Nfkb2 GeneProduct ncbigene:18034
Caspase-8 GeneProduct ncbigene:12370
TAK1 GeneProduct ncbigene:22026
NEMO GeneProduct ncbigene:16151
NAP1 GeneProduct ncbigene:11308
Tlr4 GeneProduct ncbigene:21898
MKK6 GeneProduct ncbigene:26399
Irf3 GeneProduct ncbigene:54131
Myd88 GeneProduct ncbigene:17874
IKK2 GeneProduct ncbigene:16150
Nfkb1 GeneProduct ncbigene:18033
Irf3 GeneProduct ncbigene:54131
IKK1 GeneProduct ncbigene:12675
Nfkb2 GeneProduct ncbigene:18034
IRAK-M GeneProduct ncbigene:73914
IKBa GeneProduct ncbigene:17121
Tbk1 GeneProduct ncbigene:56480
Fadd GeneProduct ncbigene:14082
Nfkb1 GeneProduct ncbigene:18033
Irak1 GeneProduct ncbigene:16179
p38MAPK GeneProduct ncbigene:26416
Irak4 GeneProduct ncbigene:266632
Tirap GeneProduct ncbigene:117149
Tlr2 GeneProduct ncbigene:24088
Rip1 GeneProduct ncbigene:19765
Tlr3 GeneProduct ncbigene:142980
Tab2 GeneProduct ncbigene:68652
IRAK-2 GeneProduct ncbigene:108960
TRIF GeneProduct ncbigene:106759
Mal GeneProduct ncbigene:17153
IKKepsilon GeneProduct ncbigene:56489

References