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J. Biol. Chem., Vol. 277, Issue 36, 33058-33067, September 6, 2002

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The Double-stranded RNA-activated Kinase, PKR, Can Phosphorylate Hepatitis D Virus Small Delta Antigen at Functional Serine and Threonine Residues^*

Chi-Wu Chen, Yeou-Guang Tsay^§, Hui-Lin Wu^¶, Chi-Hua Lee, Ding-Shinn Chen^¶, and Pei-Jer Chen^§¶

From the  Graduate Institute of Microbiology and ^§ Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan and the ^¶ Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

Hepatitis D virus (HDV) encodes two proteins, the 24-kDa small delta antigen (S-HDAg) and 27-kDa large delta antigen (L-HDAg) in its single open reading frame. Both of them had been identified as nuclear phosphoproteins. Moreover, the phosphorylated form of S-HDAg was shown to be important for HDV replication. However, the kinase responsible for S-HDAg phosphorylation remains unknown. Therefore, we employed an in-gel kinase assay to search candidate kinases and indeed identified a kinase with a molecular mass of about 68 kDa. Much evidence demonstrated this kinase to be the double-stranded RNA-activated kinase, PKR. The immunoprecipitated endogenous PKR was sufficient to catalyze S-HDAg phosphorylation, and the kinase activity disappeared in the PKR-depleted cell lysate. The S-HDAg and PKR could be co-immunoprecipitated together, and both of them co-located in the nucleolus. The LC/MS/MS analysis revealed that the serine 177, serine 180, and threonine 182 of S-HDAg were phosphorylated by PKR in vitro. This result was consistent with previous phosphoamino acid analysis indicating that serine and threonine were phosphorylation targets in S-HDAg. Furthermore, serine 177 was also shown to be the predominant phosphorylation site for S-HDAg purified the from cell line. In dominant negative PKR-transfected cells, the level of phosphorylated S-HDAg was suppressed, but replication of HDV was enhanced. Other than human immunodeficiency virus type 1 trans-activating protein (Tat), S-HDAg is another viral protein phosphorylated by PKR that may regulates HDV replication and viral response to interferon therapy.

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