title: TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin beta receptor signaling.
abstract: LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin beta receptor (LTbetaR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTbetaR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTbetaR-mediated activation of both the transcription factor NF-kappaB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-kappaB and JNK activation, which can be blocked by the dominant negative mutant of TRAF2. In these cells, LIGHT causes the recruitment of TRAF2, TRAF3, and IkappaB kinase into the LTbetaR complex. Importantly, while both NF-kappaB and JNK are activated by LIGHT in wild-type mouse embryonic fibroblasts, no activation of either of these two pathways is observed in TRAF2 null fibroblasts. However, LIGHT-induced NF-kappaB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF2-/- cells. Interestingly, in contrast to TNF signaling, the activation of both NF-kappaB and JNK by LIGHT was normal in RIP-/- and TRAF5-/- cells. Taken together, our data demonstrate that TRAF2, an important effector molecule of TNF signaling, plays a critical, nonredundant role in LIGHT-LTbetaR signaling.
authors.affiliation: Cell and Cancer Biology Branch,Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg. 10, Rm. 6N105, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D000818:Animals; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases
references.citation: J Biol Chem. 2004 Jun 18;279(25):26243-50
references.pmid: 15084608
references.citation: Annu Rev Immunol. 2000;18:621-63
references.pmid: 10837071
references.citation: Science. 1995 Sep 8;269(5229):1424-7
references.pmid: 7544915
references.citation: J Immunol. 1995 Dec 1;155(11):5280-8
references.pmid: 7594541
references.citation: J Exp Med. 1996 Mar 1;183(3):867-78
references.pmid: 8642291
references.citation: J Biol Chem. 1996 Oct 4;271(40):24934-8
references.pmid: 8798772
references.citation: Mol Cell Biol. 1996 Nov;16(11):6363-71
references.pmid: 8887665
references.citation: Cell. 1996 Nov 1;87(3):565-76
references.pmid: 8898208
references.citation: J Immunol. 1997 Feb 15;158(4):1756-62
references.pmid: 9029113
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2460-5
references.pmid: 9122217
references.citation: J Biol Chem. 1997 May 23;272(21):13471-4
references.pmid: 9153189
references.citation: J Biol Chem. 1997 May 30;272(22):14029-32
references.pmid: 9162022
references.citation: J Exp Med. 1997 Oct 6;186(7):999-1014
references.pmid: 9314550
references.citation: J Biol Chem. 1997 Dec 5;272(49):30835-40
references.pmid: 9388227
references.citation: Immunity. 1997 Nov;7(5):715-25
references.pmid: 9390694
references.citation: J Exp Med. 1998 Jan 19;187(2):147-59
references.pmid: 9432973
references.citation: J Exp Med. 1998 Jan 19;187(2):185-96
references.pmid: 9432976
references.citation: Immunity. 1998 Jan;8(1):21-30
references.pmid: 9462508
references.citation: Immunity. 1998 Mar;8(3):297-303
references.pmid: 9529147
references.citation: Annu Rev Immunol. 1998;16:111-35
references.pmid: 9597126
references.citation: Annu Rev Immunol. 1998;16:225-60
references.pmid: 9597130
references.citation: Ann N Y Acad Sci. 1998 Jun 30;851:139-46
references.pmid: 9668616
references.citation: Immunity. 1998 Jul;9(1):59-70
references.pmid: 9697836
references.citation: J Clin Invest. 1998 Sep 15;102(6):1142-51
references.pmid: 9739048
references.citation: J Biol Chem. 1998 Oct 16;273(42):27548-56
references.pmid: 9765287
references.citation: Biochem Soc Symp. 1999;64:1-12
references.pmid: 10207617
references.citation: Genes Dev. 1999 May 15;13(10):1297-308
references.pmid: 10346818
references.citation: J Biol Chem. 2000 Apr 14;275(15):11121-9
references.pmid: 10753918
references.citation: Immunity. 2000 Apr;12(4):419-29
references.pmid: 10795740
references.citation: J Biol Chem. 2000 May 12;275(19):14307-15
references.pmid: 10799510
references.citation: Cell. 2001 Feb 23;104(4):487-501
references.pmid: 11239407
references.citation: J Exp Med. 2001 Mar 5;193(5):631-6
references.pmid: 11238593
references.citation: Mol Cell. 2001 Feb;7(2):401-9
references.pmid: 11239468
references.citation: Methods Cell Biol. 2001;66:187-95
references.pmid: 11396003
references.citation: Genes Dev. 2001 Sep 15;15(18):2321-42
references.pmid: 11562344
references.citation: J Biol Chem. 2001 Sep 28;276(39):36530-4
references.pmid: 11479302
references.citation: J Immunol. 2001 Dec 1;167(11):6330-7
references.pmid: 11714797
references.citation: J Clin Invest. 2001 Dec;108(12):1771-80
references.pmid: 11748260
references.citation: Annu Rev Immunol. 2002;20:55-72
references.pmid: 11861597
references.citation: Nat Immunol. 2002 Mar;3(3):221-7
references.pmid: 11875461
references.citation: Nature. 2002 Mar 14;416(6877):194-9
references.pmid: 11894098
references.citation: Exp Cell Res. 2002 Aug 15;278(2):166-74
references.pmid: 12169272
references.citation: Bioessays. 2003 Jan;25(1):17-24
references.pmid: 12508278
references.citation: J Biol Chem. 2003 Apr 4;278(14):12006-12
references.pmid: 12556537
references.citation: Genes Dev. 2003 Apr 1;17(7):873-82
references.pmid: 12654725
references.citation: J Biol Chem. 2003 Apr 18;278(16):14363-9
references.pmid: 12571250
references.citation: EMBO Rep. 2003 Jun;4(6):623-7
references.pmid: 12776182
references.citation: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):185-91
references.pmid: 12787558
references.citation: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):193-209
references.pmid: 12787559
references.citation: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):275-88
references.pmid: 12787565
references.citation: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):289-96
references.pmid: 12787566
references.citation: Dev Biol. 2003 Nov 15;263(2):165-75
references.pmid: 14597193
references.citation: J Biol Chem. 2003 Dec 12;278(50):50523-9
references.pmid: 14517219
references.citation: J Biol Chem. 2004 Mar 12;279(11):10822-8
references.pmid: 14701813
references.citation: Trends Immunol. 2004 Jun;25(6):280-8
references.pmid: 15145317
references.citation: Annu Rev Cell Biol. 1994;10:405-55
references.pmid: 7888182