title: Epstein-Barr virus Latent Membrane Protein 2A (LMP2A)-mediated changes in Fas expression and Fas-dependent apoptosis: Role of Lyn/Syk activation.
abstract: Epstein-Barr virus Latent Membrane Protein 2A (LMP2A) is expressed in EBV-infected B cells in the germinal center, a site of significant apoptosis induced by engagement of Fas on activated B cells. Signals from the B cell receptor (BCR) protect germinal center B cells from Fas-mediated apoptosis, and since LMP2A is a BCR mimic, we hypothesized that LMP2A would also protect B cells from Fas-mediated apoptosis. Surprisingly, latently-infected human and murine B cell lines expressing LMP2A were more sensitive to Fas-mediated apoptosis, as determined by increases in Annexin-V staining, and cleavage of caspase-8, -3 and PARP. Additional studies show that LMP2A-expressing B cell lines demonstrate a Lyn- and Syk-dependent increase in sensitivity to Fas-mediated apoptosis, due to an LMP2A-dependent enhancement in Fas expression. These findings demonstrate the ability for LMP2A to directly increase a pro-apoptotic molecule and have implications for EBV latency as well as the treatment of EBV-associated malignancies.
authors.affiliation: Chicago College of Osteopathic Medicine, Department of Microbiology and Immunology, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Incrocci
authors.affiliation: College of Health Sciences, Department of Biomedical Sciences, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Samira
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Chicago College of Osteopathic Medicine, Department of Microbiology and Immunology, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Stone
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bieging
authors.affiliation: College of Health Sciences, Department of Biomedical Sciences, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Lauren A C
authors.initials: LA
authors.lastname: Alt
authors.affiliation: College of Health Sciences, Department of Biomedical Sciences, 555 31st Street, Downers Grove, IL 60515, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fay
authors.affiliation: Chicago College of Osteopathic Medicine, Department of Microbiology and Immunology, 555 31st Street, Downers Grove, IL 60515, USA. Electronic address: mswans@midwestern.edu.
authors.forename: Michelle
authors.initials: M
authors.lastname: Swanson-Mungerson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D000072377:Syk Kinase; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D014763:Viral Matrix Proteins; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
keywords: Apoptosis; B cell receptor (BCR); B cells; Epstein–Barr virus; Fas (CD95); Latency Membrane Protein 2A (LMP2A); Lyn; PARP; Syk