Epstein-Barr virus nuclear antigen 2 inhibits AID expression during EBV-driven B-cell growth.
Somatic hypermutation and class-switch recombination in germinal centers critically depend on activation-induced cytidine deaminase (AID). Deregulation of AID may lead to the aberrant activation or persistence of both genetic processes, thus contributing to the pathogenesis of B-cell lymphomas by mistargeted mutagenesis or recombination. The Epstein-Barr virus (EBV) establishes an asymptomatic latent infection in more than 90% of the human population, but it has also been linked to lymphomagenesis. A cooperative relationship of EBV and the germinal center reaction during the establishment of viral persistence has been postulated, but the contribution of EBV latent genes to the respective genetic events remains to be investigated in detail. In the present study, we show that activation of the EBV growth program has a clear inhibitory effect on AID expression, due to a negative effect of the master transcription factor of this program, EBNA2. This mechanism may counterbalance AID induction by the LMP1 protein, in order to prevent deleterious genetic changes during EBV-induced B-cell growth. EBNA2-mediated AID inhibition also provides a molecular explanation for the previously observed differences in somatic hypermutation activity in EBV-associated lymphoproliferative diseases, thus pointing to a crucial mechanism of EBV-mediated regulation of genomic integrity.
Tobollik
Stephanie
S
Institute of Clinical and Molecular Biology, GSF-Research Center for Environment and Health, Marchioninistrasse 25, 81377 München, Germany.
Meyer
Linda
L
Buettner
Maike
M
Klemmer
Sandra
S
Kempkes
Bettina
B
Kremmer
Elisabeth
E
Niedobitek
Gerald
G
Jungnickel
Berit
B
D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000276:immunology*; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics / Q000276:immunology*; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D016679:Genome, Viral / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase