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J. Biol. Chem., Vol. 277, Issue 36, 33058-33067, September 6, 2002
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From the 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.
The Double-stranded RNA-activated Kinase, PKR, Can
Phosphorylate Hepatitis D Virus Small Delta Antigen at Functional
Serine and Threonine Residues*
,
,
§¶
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
*
This work was supported in part by grants from the
National Science Council, Executive Yuan, Taiwan.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported in part by an International Research Scholar grant
from Howard Hughes Medical Institute. To whom correspondence should be
addressed. Tel.: 886-02-23123456 (ext. 7072); Fax: 886-02-23317624; E-mail: peijer@ha.mc.ntu.edu.tw.
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