title: Epstein-Barr virus nuclear antigen 1 interacts with Nm23-H1 in lymphoblastoid cell lines and inhibits its ability to suppress cell migration.
abstract: Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is expressed in the majority of latency programs in EBV-infected cells and is critical for the maintenance of EBV episomes in the infected cells. EBNA1 is also known to be involved in transcriptional activation and regulates expression of the EBV latent genes, including the EBNAs and LMP1. Thus, EBNA1 is a multifunctional protein with critical functions required for the persistence of the viral genome over successive generations, producing new daughter cells from the infected cell. We identify EBNA1 here as an interacting EBNA with the known suppressor of metastasis and cell migration, Nm23-H1. Nm23-H1 inhibits cell migration when expressed in cancer cells. We show that EBNA1 associates with Nm23-H1 in EBV-infected cells in vitro, as well as in lymphoblastoid cell lines (LCLs). Nm23-H1 predominantly localizes to the cytoplasm in BJAB and 293T cells; however, upon expression of EBNA1, Nm23-H1 is translocated to the nucleus in similar compartments to EBNA1, suggesting a potential functional role that is linked to EBNA1. Convincingly, in EBV-transformed LCLs Nm23-H1 is localized predominantly to the nucleus and colocalizes to similar compartment as EBNA1. Further, we tested the effects of EBNA1 on Nm23-H1-mediated suppression of cell migration and showed that EBNA1 rescues the suppression of cell migration mediated by Nm23-H1. These in vitro studies suggest that EBNA1 plays a critical role in regulating the activities of Nm23-H1, including cell migration, through a mechanism which involves direct interaction of this major regulator in EBV-infected cells.
authors.affiliation: Department of Microbiology and Abramson Comprehensive Cancer Center Tumor Virology Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Masanao
authors.initials: M
authors.lastname: Murakami
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D001402:B-Lymphocytes / Q000821:virology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002472:Cell Transformation, Viral; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism*; D014162:Transfection
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D054778:NM23 Nucleoside Diphosphate Kinases; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; C417029:EBV-encoded nuclear antigen 1