IRAK1 recruits IKK complex

Stable Identifier
R-HSA-937039
Type
Pathway
Species
Homo sapiens
Compartment
cytosol, plasma membrane
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
IRAK1 recruits IKK complex
Click the image above or here to open this pathway in the Pathway Browser
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
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
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
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
Participants
Events
Participates
as an event of
Event Information
Go Biological Process
positive regulation of canonical NF-kappaB signal transduction (0043123)
Orthologous Events
IRAK1 recruits IKK complex (Bos taurus)
IRAK1 recruits IKK complex (Canis familiaris)
IRAK1 recruits IKK complex (Drosophila melanogaster)
IRAK1 recruits IKK complex (Mus musculus)
IRAK1 recruits IKK complex (Rattus norvegicus)
IRAK1 recruits IKK complex (Sus scrofa)
Cross References
BioModels Database
Authored
Shamovsky, V  (2010-06-01)
Reviewed
Gillespie, ME  (2010-11-30)
Napetschnig, J  (2012-11-16)
Created
Shamovsky, V  (2010-08-25)
Cite Us!