title: Epstein-Barr virus nuclear antigen 1 (EBNA1) induced cytotoxicity in epithelial cells is associated with EBNA1 degradation and processing.
abstract: Epstein-Barr virus nuclear antigen 1 (EBNA1) has a central role in the maintenance and segregation of the Epstein-Barr virus (EBV) episome and by virtue of a glycine-alanine repeat domain is prevented from being endogenously processed for recognition by HLA class I restricted cytotoxic T lymphocytes (CTLs). We found that EBNA1 expression resulted in growth inhibition and a G2/M arrest in human squamous epithelial cell lines (SCC12F, SVK) but not epithelial cell lines of glandular origin (Hela, Ad/AH). The cytotoxicity of EBNA1 was associated with EBNA1 degradation and both these effects were blocked in SCC12F cells expressing either the anti-apoptotic bcl-2 protein or the EBV homolog of bcl-2, BHRF1. The endogenous degradation of EBNA1 in SVK epithelial cells was associated with specific CTL recognition, an effect not evident in EBNA1-expressing Hela cells. Consistent with the inability of SVK cells to tolerate EBNA1 expression, studies with a recombinant EBV demonstrated that SVK cells are unable to maintain stable virus infection, whereas Hela cells are able to efficiently establish latent EBV infection. These data have important implications for both the cellular requirements necessary to sustain a stable EBV infection and for the possible role of CTL responses in controlling EBV infection of epithelial cells.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham Medical School, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Smith
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Dawson
authors.forename: Tracy
authors.initials: T
authors.lastname: Haigh
authors.forename: Neil W
authors.initials: NW
authors.lastname: Blake
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D024882:Drug Resistance, Viral; D004847:Epithelial Cells / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D009355:Neomycin / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D013045:Species Specificity; D014764:Viral Proteins / Q000096:biosynthesis; D017735:Virus Latency
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; D019309:Epstein-Barr Virus Nuclear Antigens; D015395:Histocompatibility Antigens Class I; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins; D009355:Neomycin; C417029:EBV-encoded nuclear antigen 1