title: The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation.
abstract: 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.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Fraczek
authors.forename: Tae Whan
authors.initials: TW
authors.lastname: Kim
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yao
authors.forename: Qian
authors.initials: Q
authors.lastname: Wen
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Juliusz
authors.initials: J
authors.lastname: Pryjma
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: 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*
chemical_list: D016328:NF-kappa B; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D020930:MAP Kinase Kinase Kinases
references.citation: Science. 2003 Aug 1;301(5633):640-3
references.pmid: 12855817
references.citation: Nature. 1996 Oct 3;383(6599):443-6
references.pmid: 8837778
references.citation: Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):588-93
references.pmid: 9435236
references.citation: J Biol Chem. 2007 May 4;282(18):13552-60
references.pmid: 17337443
references.citation: J Biol Chem. 2004 Sep 24;279(39):40653-8
references.pmid: 15292196
references.citation: Gene. 1999 Apr 29;231(1-2):59-65
references.pmid: 10231569
references.citation: J Biol Chem. 2007 Mar 2;282(9):6075-89
references.pmid: 17197697
references.citation: Science. 1996 Feb 23;271(5252):1128-31
references.pmid: 8599092
references.citation: Eur J Immunol. 2008 Mar;38(3):788-96
references.pmid: 18266302
references.citation: Eur Cytokine Netw. 2000 Sep;11(3):372-8
references.pmid: 11022120
references.citation: Science. 2003 Mar 28;299(5615):2076-9
references.pmid: 12637671
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5567-72
references.pmid: 11960013
references.citation: Science. 2004 Mar 5;303(5663):1522-6
references.pmid: 15001781
references.citation: J Neurosci Res. 1998 Oct 15;54(2):169-80
references.pmid: 9788276
references.citation: Nature. 2000 Dec 7;408(6813):740-5
references.pmid: 11130078
references.citation: Nat Immunol. 2001 Aug;2(8):675-80
references.pmid: 11477402
references.citation: J Biol Chem. 2004 Jun 18;279(25):26748-53
references.pmid: 15084582
references.citation: J Immunol. 2005 Oct 1;175(7):4175-9
references.pmid: 16177054
references.citation: Mol Cell Biol. 2002 Oct;22(20):7158-67
references.pmid: 12242293
references.citation: Genes Dev. 1990 Oct;4(10):1753-65
references.pmid: 2249773
references.citation: Eur J Immunol. 2008 Mar;38(3):614-8
references.pmid: 18286571
references.citation: Mol Cell Biol. 1999 Jul;19(7):4643-52
references.pmid: 10373513
references.citation: J Exp Med. 2007 May 14;204(5):1025-36
references.pmid: 17470642
references.citation: Nature. 1999 Mar 18;398(6724):252-6
references.pmid: 10094049
references.citation: Nat Immunol. 2003 Nov;4(11):1144-50
references.pmid: 14556004
references.citation: Nature. 2003 Aug 14;424(6950):743-8
references.pmid: 12872135
references.citation: J Exp Med. 2007 May 14;204(5):1013-24
references.pmid: 17485511
references.citation: Nature. 2002 Apr 18;416(6882):750-6
references.pmid: 11923871
references.citation: Nature. 1997 Jul 24;388(6640):394-7
references.pmid: 9237759