Roles of TRAF2 and TRAF3 in Epstein-Barr virus latent membrane protein 1-induced alternative NF-kappaB activation.
Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1)-induced NF-kappaB activation is essential for EBV-transformed B cell survival. LMP1 has two C-terminal cytoplasmic domains referred to as C-Terminal Activation Regions (CTAR) 1 and 2 that activate the alternative and canonical NF-kappaB pathways, respectively. While CTAR2 activates TRAF6, IKKbeta and IKKgamma-dependent canonical NF-kappaB pathway, CTAR1 interacts with TRAF2 and TRAF3 and activates NIK and IKKalpha-dependent alternative NF-kappaB pathway involving p100 processing into functional p52. Using IKKalpha(-/-), IKKbeta(-/-), IKKgamma(-/-), TRAF2(-/-), TRAF3(-/-), TRAF6(-/-), and NIK(aly/aly) mouse embryonic fibroblasts (MEFs), potential roles of these proteins in LMP1-induced alternative NF-kappaB activation were investigated. Deficiency in IKKalpha or functional NIK, but not in IKKbeta, IKKgamma, or TRAF6, severely impaired LMP1-induced p100 processing. Notably, p100 was constitutively processed in TRAF2(-/-) or TRAF3(-/-) MEFs independently of LMP1 suggesting that TRAF2 or TRAF3 may play a regulatory role in p100 processing. Subsequently, TRAF2 or TRAF3 over-expression in HEK293 cells significantly blocked LMP1-induced p100 processing. The LMP1 CTAR1 expression in 293HEK cells activated the alternative p65/p52 complex while CTAR2 failed to do so. Taken together, LMP1 activates alternative NF-kappaB pathway through functional NIK and IKKalpha that is regulated by TRAF2 or TRAF3.
Song
Yoon-Jae
YJ
Department of Life Science, Kyungwon University, Kyeonggi-Do, Korea. songyj@kyungwon.ac.kr
Kang
Myung-Soo
MS
D000818:Animals; D002478:Cells, Cultured; D004720:Endonucleases; D005347:Fibroblasts; D004854:Herpesvirus 4, Human / Q000472:pathogenicity* / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000097782:NF-kappaB-Inducing Kinase
D004720:Endonucleases; D051550:I-kappa B Kinase; D016328:NF-kappa B; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D014763:Viral Matrix Proteins; D000097782:NF-kappaB-Inducing Kinase; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C095221:SND1 protein, human; C490640:Snd1 protein, mouse