Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis.
Animals
Cell Differentiation
Cell Line, Tumor
Cell Transformation, Viral
DNA-Binding Proteins
/ genetics
Disease Models, Animal
Epstein-Barr Virus Infections
/ pathology
Epstein-Barr Virus Nuclear Antigens
/ metabolism
Fibroblasts
Herpesvirus 4, Human
/ metabolism
Humans
Lymphoma, B-Cell
/ pathology
Mice
Mice, Knockout
Plasma Cells
/ pathology
Primary Cell Culture
Trans-Activators
/ genetics
Viral Matrix Proteins
/ metabolism
Viral Proteins
/ metabolism
B cell lymphomagenesis
EBNA
Epstein-Barr virus
LMP1
plasma cell differentiation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
23 06 2020
23 06 2020
Historique:
pubmed:
12
6
2020
medline:
29
8
2020
entrez:
12
6
2020
Statut:
ppublish
Résumé
Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.
Identifiants
pubmed: 32522871
pii: 1921139117
doi: 10.1073/pnas.1921139117
pmc: PMC7322082
doi:
Substances chimiques
DNA-Binding Proteins
0
EBNA-2 protein, Human herpesvirus 4
0
EBNA-3A antigen
0
EBV-associated membrane antigen, Epstein-Barr virus
0
Ebf1 protein, mouse
0
Epstein-Barr Virus Nuclear Antigens
0
Rag2 protein, mouse
0
Trans-Activators
0
Viral Matrix Proteins
0
Viral Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14421-14432Subventions
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008584/1
Pays : United Kingdom
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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