TLR signaling pathways
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TLR2-, TLR3- and TLR4-mediated signaling
TLR4 activates both the MyD88- and the TRIF-dependent pathways. TIRAP and TRAM are required for the activation of the MyD88- and the TRIF-dependent pathways, respectively.
MyD88 recruits TRAF6 and members of the IRAK family. TRAF6, together with Ubc13 and Uev1A, activates the TAK1 complex via K63-linked ubiquitination (Ub).
The activated TAK1 complex then activates the IKK complex consisting of IKK?, IKK? and NEMO, which catalyzes the phosphorylation of I?B proteins (P).
I?Bs are destroyed by the proteasome-dependent pathway, allowing NF-?B (RelA?p50 heterodimer) to translocate into the nucleus (canonical pathway).
Simultaneously, the TAK1 complex activates the MAPK pathway, which results in the phosphorylation (P) and activation of AP-1.
NF-?B and AP-1 control inflammatory responses through the induction of inflammatory cytokines. TRIF recruits TRAF3, which then interacts with TBK1 and IKKi. These kinases mediate phosphorylation of IRF3 (P).
Phosphorylated IRF3 dimerizes and translocates into the nucleus to regulate transcription.
TRIF also interacts with TRAF6 and RIP1, which mediate NF-?B activation.
Activation of the IRF3, NF-?B and MAPK pathways is required for induction of type I IFN, particularly IFN-?.
There are two types of NF-?B activation in TLR4 signaling: the MyD88-dependent pathway, which mediates early phase activation of NF-?B and the TRIF-dependent pathway, which mediates the late phase activation of NF-?B.
TLR3, which resides in endosomal vesicles, utilizes TRIF, whereas TLR2 utilizes TIRAP and MyD88.
Pathology
Three human primary immunodeficiencies associated with impaired TLR signalling were described.
Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-kappaB (NF-kappaB) activation.
- X-linked recessive
- autosomal dominant
These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients? cells showed an impaired, but not abolished, NF-kappaB activation in response to a large set of stimuli, including TLR agonists.
autosomal recessive amorphic mutations in IRAK4
- no developmental defect
- more restricted spectrum of infectious diseases
- pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive
In vitro studies carried out with these patients? cells showed a specific impairment of the Toll-interleukin-1 receptor (TIR)-interleukin-1 receptor associated kinase (IRAK) signalling pathway.
NF-kappaB- and mitogen activated protein kinase (MAPKs) pathways are impaired in response to all TIR agonists tested.
TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.
Tumor-necrosis factor receptor-associated factor 3 (TRAF3) is an essential component of the TLR-signaling pathway, being a crucial regulator in the induction of TLR-specific inflammatory responses.
See also
TLRs
- TLR signaling pathway diseases
References
Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007 Oct 26; PMID: 18029230
Hoebe K, Beutler B. TRAF3: a new component of the TLR-signaling apparatus. Trends Mol Med. 2006 May;12(5):187-9. PMID: 16621716
Puel A, Yang K, Ku CL, von Bernuth H, Bustamante J, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL. Heritable defects of the human TLR signalling pathways. J Endotoxin Res. 2005;11(4):220-4. PMID: 16176658