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.
Highlights
Epstein-Barr virus (EBV) usually infects and replicates in oropharyngeal epithelial cells [1,2,3]
The eukaryotic linear motif and Netphos 2.0 tool predicted the existence of a putative motif for ERK2-directed proline-dependent phosphorylation at a.a. 381-384 (PRSP), and a potential extracellular signal-regulated kinase (ERK) docking site at a.a. 521-528RRGTALAI) on the surface of EBNA1 [26] (Figure 1A)
It is experimentally proven that casein kinase 2 (CK2), CDKs, and the only EBV kinase analogue to cellular CDKs (BGLF4) can phosphorylate multiple serine residues on EBNA1 [31] [23] [32, 33]
Summary
Epstein-Barr virus (EBV) usually infects and replicates in oropharyngeal epithelial cells [1,2,3]. EBV-encoded nuclear antigen 1 (EBNA1) is essential for EBV episome persistence and transcription in dividing cells [13,14,15,16]. EBNA1 contains three essential domains: arginineglycine-rich domain 1 (RG1) (a.a. 61-83), RG2 (a.a. 325376), and dimerization/cognate DNA binding domain (DD/DBD) (a.a. 459-607) [17, 18]. Both RG1 and RG2 are necessary and sufficient for EBNA1 to associate with its target DNA, and are essential for EBNA1-dependent transcription of latent genes and genome persistence [17, 19,20,21,22]. An EBNA1 inhibitor can potentially terminate latent EBV infection and cancel any effect of EBV in non-malignant and malignant diseases
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