Epstein-Barr virus latent membrane protein 1 modulates distinctive NF- kappaB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression.
Epstein-Barr Virus (EBV) latent membrane protein 1 (LMP1) is required for EBV B-lymphocyte transformation, transforms rodent fibroblasts, and can induce lymphoma and epithelial hyperplasia in transgenic mice. Two domains have been identified within the intracellular carboxy terminus that can activate NF-kappaB, C-terminus-activating region 1 (CTAR1) and CTAR2, through interactions with tumor necrosis receptor-associated factors (TRAFs). CTAR1 can activate both the canonical and noncanonical NF-kappaB pathways and has unique effects on cellular gene expression. The epidermal growth factor receptor (EGFR) is highly induced by LMP1-CTAR1 in epithelial cells through activation of a novel NF-kappaB form containing p50 homodimers and Bcl-3. To further understand the regulation of NF-kappaB in CTAR1-induced EGFR expression, we evaluated the ability of CTAR1 to induce EGFR in mouse embryonic fibroblasts (MEFs) defective for different NF-kappaB effectors. CTAR1-mediated EGFR induction required the NF-kappaB-inducing kinase (NIK) but not the IkappaB kinase (IKK) complex components that regulate canonical or noncanonical NF-kappaB pathways. CTAR1-mediated induction of nuclear p50 occurred in IKKbeta-, IKKgamma-, and NIK-defective MEFs, indicating that this induction is not dependent on the canonical or noncanonical NF-kappaB pathways. EGFR and nuclear p50 were expressed at high levels in TRAF2(-/-) fibroblasts and were not induced by CTAR1. In TRAF3(-/-) MEFs, CTAR1 induced nuclear p50 but did not affect basal levels of STAT3 serine phosphorylation or induce EGFR expression. EGFR was induced by LMP1 in TRAF6(-/-) MEFs. These findings suggest that this novel NF-kappaB pathway is differentially regulated by TRAF2 and TRAF3, and that distinct interactions of LMP1 and its effectors regulate LMP1-mediated gene expression.
Kung
Che-Pei
CP
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Raab-Traub
Nancy
N
D000818:Animals; D066246:ErbB Receptors / Q000096:biosynthesis*; D005347:Fibroblasts / Q000821:virology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*; D053585:Virus Attachment; D000097782:NF-kappaB-Inducing Kinase
D066246:ErbB Receptors; D051550:I-kappa B Kinase; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D000097782:NF-kappaB-Inducing Kinase; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C494087:Stat3 protein, mouse; C073701:Nfkb1 protein, mouse
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