Reactome | IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation

IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation

Stable Identifier

R-HSA-975163

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, endosome membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 7/8 (TLR7/8) Cascade (Homo sapiens)
      - MyD88 dependent cascade initiated on endosome (Homo sapiens)
        
        TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (Homo sapiens)
        
        IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (Homo sapiens)
    - Toll Like Receptor 9 (TLR9) Cascade (Homo sapiens)
      - MyD88 dependent cascade initiated on endosome (Homo sapiens)
        
        TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (Homo sapiens)
        
        IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (Homo sapiens)

General

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IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation

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Although IRAK-1 was originally thought to be a key mediator of TRAF6 activation in the IL1R/TLR signaling (Dong W et al. 2006), recent studies showed that IRAK-2, but not IRAK-1, led to TRAF6 polyubiquitination (Keating SE et al 2007). IRAK-2 loss-of-function mutants, with mutated TRAF6-binding motifs, could no longer activate NF-kB and could no longer stimulate TRAF-6 ubiquitination (Keating SE et al 2007). Furthermore, the proxyvirus protein A52 - an inhibitor of all IL-1R/TLR pathways to NF-kB activation, was found to interact with both IRAK-2 and TRAF6, but not IRAK-1. Further work showed that A52 inhibits IRAK-2 functions, whereas association with TRAF6 results in A52-induced MAPK activation. The strong inhibition effect of A52 was also observed on the TLR3-NFkB axis and this observation led to the discovery that IRAK-2 is recruited to TLR3 to activate NF-kB (Keating SE et al 2007). Thus, A52 possibly inhibits MyD88-independent TLR3 pathways to NF-kB via targeting IRAK-2 as it does for other IL-1R/TLR pathways, although it remains unclear how IRAK-2 is involved in TLR3 signaling.

IRAK-2 was shown to have two TRAF6 binding motifs that are responsible for initiating TRAF6 signaling transduction (Ye H et al 2002).

Literature References

PubMed ID	Title	Journal	Year
17878161	IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination Maloney, GM, Bowie, AG, Keating, SE, Moran, EM	J Biol Chem	2007
16831874	The IRAK-1-BCL10-MALT1-TRAF6-TAK1 cascade mediates signaling to NF-kappaB from Toll-like receptor 4 Zou, T, Liu, Z, Liu, Y, Xiao, H, Peng, J, Chen, L, Bu, Y, Dong, W, Qi, Y, Li, W	J Biol Chem	2006
12140561	Distinct molecular mechanism for initiating TRAF6 signalling Vologodskaia, M, Kobayashi, T, Wu, H, Cirilli, M, Lamothe, B, Arron, JR, Pike, JW, Ye, H, Shevde, NK, Choi, Y, Yim, M, Darnay, BG, Du, K, Dzivenu, OK, Segal, D, Singh, S	Nature	2002