title: Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling.
abstract: The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.
authors: Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL 33136, USA.
authors: Noula
authors: N
authors: Shembade
authors: Nicole S
authors: NS
authors: Harhaj
authors: Daniel J
authors: DJ
authors: Liebl
authors: Edward W
authors: EW
authors: Harhaj
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; C523855:TAX1BP1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases
references: Immunity. 2006 Dec;25(6):929-40
references: 17137798
references: J Virol. 1998 Oct;72(10):8332-7
references: 9733879
references: J Biol Chem. 2007 Feb 9;282(6):4102-12
references: 17135271
references: J Biol Chem. 2007 Feb 9;282(6):4185-92
references: 17145747
references: Cancer Res. 2007 Feb 1;67(3):1072-81
references: 17283140
references: J Biol Chem. 1997 Oct 10;272(41):25816-23
references: 9325311
references: Genes Dev. 2000 Apr 1;14(7):854-62
references: 10766741
references: Annu Rev Immunol. 2000;18:621-63
references: 10837071
references: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9567-72
references: 10920205
references: Science. 2000 Sep 29;289(5488):2350-4
references: 11009421
references: Cell. 2000 Oct 13;103(2):351-61
references: 11057907
references: AIDS Res Hum Retroviruses. 2000 Nov 1;16(16):1689-94
references: 11080811
references: Mol Cell. 2001 Feb;7(2):401-9
references: 11239468
references: Mol Cell Biol. 2001 Jun;21(12):3986-94
references: 11359906
references: J Biol Chem. 2001 Sep 28;276(39):36530-4
references: 11479302
references: Sci STKE. 1999 Oct 26;1999(5):RE1
references: 11865184
references: Mech Dev. 2002 Dec;119(2):239-49
references: 12464436
references: Nucleic Acids Res. 2003 Jan 1;31(1):278-81
references: 12520002
references: Science. 2003 Jan 10;299(5604):247-51
references: 12522250
references: J Mol Biol. 2003 Feb 7;326(1):105-15
references: 12547194
references: J Biol Chem. 2003 Mar 28;278(13):11376-85
references: 12536145
references: Virology. 2005 Mar 1;333(1):145-58
references: 15708600
references: Biochem J. 2005 Apr 1;387(Pt 1):47-55
references: 15527421
references: IUBMB Life. 2005 Feb;57(2):83-91
references: 16036567
references: Nat Rev Immunol. 2005 Oct;5(10):749-59
references: 16175180
references: Nat Immunol. 2005 Nov;6(11):1087-95
references: 16186825
references: Mol Cell Biol. 2005 Dec;25(23):10391-406
references: 16287853
references: Genes Dev. 2005 Nov 15;19(22):2668-81
references: 16260493
references: J Biol Chem. 2006 Jan 27;281(4):2095-103
references: 16306043
references: Nat Immunol. 2006 Apr;7(4):411-7
references: 16501569
references: Cell. 2006 May 19;125(4):665-77
references: 16713561
references: J Biol Chem. 2006 Jul 7;281(27):18482-8
references: 16684768
references: Mol Cell Biol. 2006 Aug;26(16):6272-82
references: 16880535
references: Sci STKE. 2006 Oct 17;2006(357):re13
references: 17047224
references: Nature. 2003 Aug 14;424(6950):793-6
references: 12917689
references: Biochem J. 2004 Mar 15;378(Pt 3):727-34
references: 14748687
references: Genes Dev. 1999 Apr 15;13(8):1015-24
references: 10215628
references: Oncogene. 1999 Jul 22;18(29):4182-90
references: 10435631
references: J Biol Chem. 1999 Aug 13;274(33):22911-4
references: 10438454
references: Cell Signal. 2007 Mar;19(3):646-57
references: 17052891
references: Nature. 2004 Aug 5;430(7000):694-9
references: 15258597
references: Genes Dev. 2004 Sep 15;18(18):2195-224
references: 15371334
references: Nat Immunol. 2004 Oct;5(10):1052-60
references: 15334086
references: J Virol. 2004 Nov;78(21):11686-95
references: 15479810
references: J Biol Chem. 1992 Sep 5;267(25):17971-6
references: 1381359
references: Science. 1993 Mar 26;259(5103):1912-5
references: 8096091
references: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9792-6
references: 9275204
references: Mol Cell. 1998 Aug;2(2):253-8
references: 9734363
references: J Biol Chem. 2004 Dec 31;279(53):55161-7
references: 15496400