MEKK4 sequesters RIP2 to dictate NOD2 signal specificity.
The Crohn's-disease-susceptibility protein, NOD2, coordinates signaling responses upon intracellular exposure to bacteria. Although NOD2 is known to activate NFkappaB, little is known about the molecular mechanisms by which NOD2 coordinates functionally separate signaling pathways such as NFkappaB, JNK, and p38 to regulate cytokine responses. Given that one of the characteristics of Crohn's disease is an altered cytokine response to normal bacterial flora, the coupling of signaling pathways could be important for Crohn's-disease pathophysiology. We find that a MAP3K, MEKK4, binds to RIP2 to sequester RIP2 from the NOD2 signaling pathway. This MEKK4:RIP2 complex dissociates upon exposure to the NOD2 agonist, MDP, allowing NOD2 to bind to RIP2 and activate NFkappaB. MEKK4 thus sequesters RIP2 to inhibit the NOD2:RIP2 complex from activating NFkappaB signaling pathways, and Crohn's-disease-associated NOD2 polymorphisms cannot compete with MEKK4 for RIP2 binding. Lastly, we find that MEKK4 helps dictate signal specificity downstream of NOD2 activation as knockdown of MEKK4 in macrophages exposed to MDP causes increased NFkappaB activity, absent p38 activity, and hyporesponsiveness to TLR2 and TLR4 agonists. These biochemical findings suggest that basal inhibition of the NOD2-driven NFkappaB pathway by MEKK4 could be important in the pathogenesis of Crohn's disease.
Clark
Nivedita M
NM
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Marinis
Jill M
JM
Cobb
Brian A
BA
Abbott
Derek W
DW
D002460:Cell Line; D006706:Homeostasis; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D048728:MAP Kinase Kinase Kinase 1; D048730:MAP Kinase Kinase Kinase 2; D048748:MAP Kinase Kinase Kinase 3; D048768:MAP Kinase Kinase Kinase 4
Immunity. 2008 Feb;28(2):246-57
18261938
Gut. 2005 Nov;54(11):1515-8
16227353
Biochem J. 2007 Jun 1;404(2):179-90
17348859
Nature. 2007 Mar 29;446(7135):557-61
17361131
PLoS Pathog. 2005 Nov;1(3):279-85
16322770
Immunity. 2006 Sep;25(3):473-85
16949315
Genes Dev. 2004 Sep 15;18(18):2195-224
15371334
Annu Rev Biochem. 2005;74:355-83
15952891
Nat Immunol. 2004 Aug;5(8):800-8
15220916
J Biol Chem. 2007 Dec 14;282(50):36223-9
17947236
Mol Cell Biol. 2007 Sep;27(17):6012-25
17562858
Curr Biol. 2004 Dec 29;14(24):2217-27
15620648
Nature. 2002 Mar 14;416(6877):194-9
11894098
Immunology. 2008 Apr;123(4):600-5
18028374
Mol Cell. 2004 May 7;14(3):289-301
15125833
EMBO J. 2004 Apr 7;23(7):1576-86
15044949
Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19440-5
18032608
Gastroenterology. 2002 Jul;123(1):106-11
12105838
Nat Immunol. 2007 Feb;8(2):198-205
17187069
Mol Cell Biol. 2005 Oct;25(20):8948-59
16199873
Science. 2005 Feb 4;307(5710):734-8
15692052
J Biol Chem. 2003 Mar 14;278(11):8869-72
12527755
Nat Rev Immunol. 2006 Jan;6(1):9-20
16493424
Immunol Rev. 2005 Aug;206:277-95
16048555
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3846-51
15731347
N Engl J Med. 2002 Aug 8;347(6):417-29
12167685
Nat Immunol. 2006 Dec;7(12):1250-7
17110941
Science. 2005 Feb 4;307(5710):731-4
15692051
J Immunol. 2007 Feb 15;178(4):2380-6
17277144
J Biol Chem. 2003 Feb 21;278(8):5509-12
12514169