Latent membrane protein 1 of Epstein-Barr virus induces CD83 by the NF-kappaB signaling pathway.
Epstein-Barr virus (EBV) infects human resting B cells and transforms them in vitro into continuously growing lymphoblastoid cell lines (LCLs). EBV nuclear antigen 2 (EBNA2) is one of the first viral proteins expressed after infection. It is able to transactivate viral as well as cellular target genes by interaction with cellular transcription factors. EBNA2 target genes can be studied easily by using an LCL (ER/EB2-5) in which wild-type EBNA2 is replaced by an estrogen-inducible EBNA2. Since the cell surface molecule CD83, a member of the immunoglobulin superfamily and a marker for mature dendritic cells, appeared on the surface of ER/EB2-5 cells within 3 h after the addition of estrogen, we analyzed the regulation of CD83 induction by EBV in more detail. Despite its rapid induction, CD83 turned out to be an indirect target gene of EBNA2. We could show that the viral latent membrane protein 1 (LMP1) is responsible for the induction of CD83 by using an LCL expressing a ligand- or antibody-inducible recombinant nerve growth factor receptor-LMP1 fusion protein. The inducibility of the CD83 promoter by LMP1 was mediated by the activation of NF-kappaB, as seen by use of luciferase reporter assays using the CD83 promoter and LMP1 mutants. Additionally, fusion constructs of the transmembrane domain of LMP1 and the intracellular signaling domain of CD40, TNF-R1, and TNF-R2 likewise transactivated the CD83 promoter via NF-kappaB. Our studies show that CD83 is also a target of the NF-kappaB signaling pathway in B cells.
Dudziak
Diana
D
Institute of Clinical Molecular Biology and Tumor Genetics, GSF-National Research Center for EnvironmentHealth, D-81377 Munich, Germany. dudziak@gsf.edu
Kieser
Arnd
A
Dirmeier
Ulrike
U
Nimmerjahn
Falk
F
Berchtold
Susanne
S
Steinkasserer
Alexander
A
Marschall
Gabriele
G
Hammerschmidt
Wolfgang
W
Laux
Gerhard
G
Bornkamm
Georg W
GW
D015703:Antigens, CD; D001402:B-Lymphocytes; D019013:CD40 Antigens / Q000378:metabolism; D002461:Cell Line, Transformed; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D017353:Gene Deletion; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins; D000097802:CD83 Antigen
D015703:Antigens, CD; D019013:CD40 Antigens; D019309:Epstein-Barr Virus Nuclear Antigens; D004967:Estrogens; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D000097802:CD83 Antigen; C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus