IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation

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R-HSA-975144
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Homo sapiens
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The role of IRAK1 kinase activity in the activation of NF-kappa-B by IL-1/TLR is still uncertain. It has been shown that a kinase-dead IRAK1 mutants can still activate NF-kappa-B. Furthermore, stimulation of IRAK1-deficient I1A 293 cells with LMP1 (latent membrane protein 1- a known viral activator of NF-kappa-B) leads to TRAF6 polyubiquitination and IKKbeta activation [Song et al 2006]. On the other hand, IRAK1 enhances p65 Ser536 phosphorylation [Song et al 2006] and p65 binding to the promoter of NF-kappa-B dependent target genes [Liu G et al 2008].

IRAK1 has also been shown to be itself Lys63-polyubiquitinated (probably by Pellino proteins, which have E3 ligase activity). Mutation of the ubiquitination sites on IRAK1 prevented interaction with the NEMO subunit of IKK complex and subsequent IL-1/TLR-induced NF-kappa-B activation [Conze et al 2008]. These data suggest that kinase activity of IRAK1 is not essential for its ability to activate NF-kappa-B, while its Lys63-polyubuquitination allows IRAK1 to bind NEMO thus facilitating association of TRAF6 and TAK1 complex with IKK complex followed by induction of NF-kappa-B.

Upon IL-1/TLR stimulation IRAK1 protein can undergo covalent modifications including phosphorylation [Kollewe et al 2004], ubiquitination [Conze DB et al 2008] and sumoylation [Huang et al 2004]. Depending upon the nature of its modification, IRAK1 may perform distinct functions including activation of IRF5/7 [Uematsu et al 2005, Schoenemeyer et al 2005], NF-kappa-B [Song et al 2006], and Stat1/3 [Huang et al 2004, Nguyen et al 2003].

Literature References
PubMed ID Title Journal Year
14661019 Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3

Liu, ZG, Cheng, J, Lin, Y, Huang, Q, Walker, GC, Yang, J, Su, B

Nat Immunol 2004
15767370 Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction

Takeuchi, O, Yamamoto, M, Matsuda, M, Ishii, KJ, Sato, S, Akira, S, Kawai, T, Kato, H, Coban, C, Hirotani, T, Uematsu, S, Takeshita, F

J Exp Med 2005
16477006 IL-1 receptor-associated kinase 1 is critical for latent membrane protein 1-induced p65/RelA serine 536 phosphorylation and NF-kappaB activation

Kieff, E, Jen, KY, Song, YJ, Cahir-McFarland, E, Soni, V

Proc Natl Acad Sci U S A 2006
14625308 Sequential autophosphorylation steps in the interleukin-1 Receptor-associated Kinase-1 Regulate its Availability as an Adapter in Interleukin-1 Signaling

Wesche, H, Li, S, Martin, MU, Knop, J, Neumann, D, Cao, P, Mackensen, AC, Kollewe, C

J Biol Chem 2004
12856330 IRAK-dependent phosphorylation of Stat1 on serine 727 in response to interleukin-1 and effects on gene expression

Stark, GR, Jiang, Z, Li, X, Qing, Y, Bayes, J, Chatterjee-Kishore, M, Nguyen, H, Ramana, CV, Commane, M

J Interferon Cytokine Res 2003
18347055 Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation

Conze, DB, Landstrom, A, Ashwell, JD, Thomas, JA, Wu, CJ

Mol Cell Biol 2008
15695821 The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling

Fitzgerald, KA, Latz, E, Barnes, BJ, Goutagny, N, Mancl, ME, Golenbock, DT, Pitha-Rowe, PM, Schoenemeyer, A

J Biol Chem 2005
18276832 Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity

Park, YJ, Abraham, E, Liu, G

FASEB J 2008
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