title: ERK2 phosphorylation of EBNA1 serine 383 residue is important for EBNA1-dependent transactivation.
abstract: Functional inhibition of Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) can cause the death of EBV infected cells. In this study, a bioinformatics tool predicted the existence of putative extracellular signal-regulated kinase (ERK) docking and substrate consensus sites on EBNA1, suggesting that ERK2 could bind to and phosphorylate EBNA1. In accordance, ERK2 was found to phosphorylate EBNA1 serine 383 in a reaction suppressed by H20 (a structural congener of the ERK inhibitor), U0126 (an inhibitor of MEK kinase), and mutations at substrate (S383A) or putative ERK docking sites. Wild-type (S383) and phosphomimetic (S383D) EBNA1 demonstrated comparable transactivation function, which was suppressed by H20 or U0126. In contrast, non-phosphorylated EBNA1 mutants displayed significantly impaired transactivation activity. ERK2 knock-down by siRNA, or treatment with U0126 or H20 repressed EBNA1-dependent transactivation.Collectively, these data indicate that blocking ERK2-directed phosphorylation can suppress EBNA1-transactivation function in latent EBV-infected cells, validating ERK2 as a drug target for EBV-associated disorders.
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Ka-Won
authors.initials: KW
authors.lastname: Noh
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Joo
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.affiliation: BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Jongno-gu, Seoul, Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.|Samsung Biomedical Research Institute (SBRI), Samsung Medical Center and Sungkyunkwan University, Seoul, Korea.|BioMembrane Plasticity Research Center (MPRC), Seoul National University College of Medicine, Jongno-gu, Seoul, Korea.
authors.forename: Myung-Soo
authors.initials: MS
authors.lastname: Kang
mesh_terms: D045744:Cell Line, Tumor; D020031:Epstein-Barr Virus Infections / Q000378:metabolism*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D004854:Herpesvirus 4, Human; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D012694:Serine; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; C417029:EBV-encoded nuclear antigen 1
keywords: EBNA1; ERK; Epstein-Barr virus; inhibitor; phosphorylation