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TLR signaling pathways

Thursday 26 January 2006

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 IKKα, IKKβ and NEMO, which catalyzes the phosphorylation of IκB proteins (P).

- IκBs are destroyed by the proteasome-dependent pathway, allowing NF-κB (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-κB 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-κB activation.

- Activation of the IRF3, NF-κB and MAPK pathways is required for induction of type I IFN, particularly IFN-β.

- There are two types of NF-κB activation in TLR4 signaling: the MyD88-dependent pathway, which mediates early phase activation of NF-κB and the TRIF-dependent pathway, which mediates the late phase activation of NF-κB.

- 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.

TRAF3

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

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