The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation.
Two parallel interleukin-1 (IL-1)-mediated signaling pathways have been uncovered for IL-1R-TLR-mediated NFkappaB activation: TAK1-dependent and MEKK3-dependent pathways, respectively. The TAK1-dependent pathway leads to IKKalpha/beta phosphorylation and IKKbeta activation, resulting in classic NFkappaB activation through IkappaBalpha phosphorylation and degradation. The TAK1-independent MEKK3-dependent pathway involves IKKgamma phosphorylation and IKKalpha activation, resulting in NFkappaB activation through dissociation of phosphorylated IkappaBalpha from NFkappaB without IkappaBalpha degradation. IL-1 receptor-associated kinase 4 (IRAK4) belongs to the IRAK family of proteins and plays a critical role in IL-1R/TLR-mediated signaling. IRAK4 kinase-inactive mutant failed to mediate the IL-1R-TLR-induced TAK1-dependent NFkappaB activation pathway, but mediated IL-1-induced TAK1-independent NFkappaB activation and retained the ability to activate substantial gene expression, indicating a structural role of IRAK4 in mediating this alternative NFkappaB activation pathway. Deletion analysis of IRAK4 indicates the essential structural role of the IRAK4 death domain in receptor proximal signaling for mediating IL-1R-TLR-induced NFkappaB activation.
Fraczek
Jerzy
J
Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Kim
Tae Whan
TW
Xiao
Hui
H
Yao
Jianhong
J
Wen
Qian
Q
Li
Yali
Y
Casanova
Jean-Laurent
JL
Pryjma
Juliusz
J
Li
Xiaoxia
X
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D005347:Fibroblasts; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
D016328:NF-kappa B; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D020930:MAP Kinase Kinase Kinases
Science. 2003 Aug 1;301(5633):640-3
12855817
Nature. 1996 Oct 3;383(6599):443-6
8837778
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):588-93
9435236
J Biol Chem. 2007 May 4;282(18):13552-60
17337443
J Biol Chem. 2004 Sep 24;279(39):40653-8
15292196
Gene. 1999 Apr 29;231(1-2):59-65
10231569
J Biol Chem. 2007 Mar 2;282(9):6075-89
17197697
Science. 1996 Feb 23;271(5252):1128-31
8599092
Eur J Immunol. 2008 Mar;38(3):788-96
18266302
Eur Cytokine Netw. 2000 Sep;11(3):372-8
11022120
Science. 2003 Mar 28;299(5615):2076-9
12637671
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72
11960013
Science. 2004 Mar 5;303(5663):1522-6
15001781
J Neurosci Res. 1998 Oct 15;54(2):169-80
9788276
Nature. 2000 Dec 7;408(6813):740-5
11130078
Nat Immunol. 2001 Aug;2(8):675-80
11477402
J Biol Chem. 2004 Jun 18;279(25):26748-53
15084582
J Immunol. 2005 Oct 1;175(7):4175-9
16177054
Mol Cell Biol. 2002 Oct;22(20):7158-67
12242293
Genes Dev. 1990 Oct;4(10):1753-65
2249773
Eur J Immunol. 2008 Mar;38(3):614-8
18286571
Mol Cell Biol. 1999 Jul;19(7):4643-52
10373513
J Exp Med. 2007 May 14;204(5):1025-36
17470642
Nature. 1999 Mar 18;398(6724):252-6
10094049
Nat Immunol. 2003 Nov;4(11):1144-50
14556004
Nature. 2003 Aug 14;424(6950):743-8
12872135
J Exp Med. 2007 May 14;204(5):1013-24
17485511
Nature. 2002 Apr 18;416(6882):750-6
11923871
Nature. 1997 Jul 24;388(6640):394-7
9237759