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Journal of Virology, October 2008, p. 9345-9358, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00656-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

ERK1/2-Mediated Phosphorylation of Small Hepatitis Delta Antigen at Serine 177 Enhances Hepatitis Delta Virus Antigenomic RNA Replication {triangledown}

Yen-Shun Chen,1 Wen-Hung Huang,2 Shiao-Ya Hong,1 Yeou-Guang Tsay,3 and Pei-Jer Chen1,2*

Graduate Institute of Microbiology,1 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University,2 Institute of Biochemistry and Molecular Biology, National Yang-Ming University School of Life Sciences, Taipei, Taiwan3

Received 25 March 2008/ Accepted 10 July 2008

The small hepatitis delta virus (HDV) antigen (SHDAg) plays an essential role in HDV RNA double-rolling-circle replication. Several posttranslational modifications (PTMs) of HDAgs, including phosphorylation, acetylation, and methylation, have been characterized. Among the PTMs, the serine 177 residue of SHDAg is a phosphorylation site, and its mutation preferentially abolishes HDV RNA replication from antigenomic RNA to genomic RNA. Using coimmunoprecipitation analysis, the cellular kinases extracellular signal-related kinases 1 and 2 (ERK1/2) are found to be associated with the Flag-tagged SHDAg mutant (Ser-177 replaced with Cys-177). In an in vitro kinase assay, serine 177 of SHDAg was phosphorylated directly by either Flag-ERK1 or Flag-ERK2. Activation of endogenous ERK1/2 by a constitutively active MEK1 (hemagglutinin-AcMEK1) increased phosphorylation of SHDAg at Ser-177; this phosphorylation was confirmed by immunoblotting using an antibody against phosphorylated S177 and mass spectrometric analysis. Interestingly, we found an increase in the HDV replication from antigenomic RNA to genomic RNA but not in that from genomic RNA to antigenomic RNA. The Ser-177 residue was critical for SHDAg interaction with RNA polymerase II (RNAPII), the enzyme proposed to regulate antigenomic RNA replication. These results demonstrate the role of ERK1/2-mediated Ser-177 phosphorylation in modulating HDV antigenomic RNA replication, possibly through RNAPII regulation. The results may shed light on the mechanisms of HDV RNA replication.

* Corresponding author. Mailing address: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. Phone: 886-02-23123456, ext. 7072. Fax: 886-02-23317624. E-mail: peijerchen{at}ntu.edu.tw

{triangledown} Published ahead of print on 16 July 2008.

Journal of Virology, October 2008, p. 9345-9358, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00656-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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