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J. Biol. Chem., Vol. 278, Issue 18, 15541-15549, May 2, 2003
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From the Fibrinogen-like protein 2/fibroleukin
(Fgl2) plays a pivotal role in the pathogenesis of both
experimental and human fulminant hepatic failure. We have reported
recently that the nucleocapsid (N) protein from strains of murine
hepatitis virus (MHV-3, MHV-A59), which cause massive hepatocellular
necrosis but not from strains (MHV-JHM, MHV-2) which do not produce
serious liver disease, induces transcription of fgl2. The
purpose of the present study was to characterize both viral and host
factor(s) necessary for viral induced transcription of
fgl2. Mutation of residues Gly-12, Pro-38, Asn-40, Gln-41,
and Asn-42 within domain 1 of the N protein of MHV-A59 to their
corresponding residues found in MHV-2 abrogated fgl2
transcription, whereas mutation of other N protein domains, including a
protein expressed from an internal reading frame (I protein), did not
affect fgl2 gene transcription. We then examined the
Induction of Prothrombinase fgl2 by the Nucleocapsid
Protein of Virulent Mouse Hepatitis Virus Is Dependent on Host
Hepatic Nuclear Factor-4
*
§¶,
,,,,, and**
Department of Infectious Disease, Tongji
Hospital, Institute of Immunology, Tongji Medical College of Huazhong
University of Science and Technology, Wuhan, 430030, China and
Multi-Organ Transplant Program and Department of Medicine and
Pathology, the Toronto General Hospital, University of Toronto,
Toronto M5G 2C4, Canada
372
to 306 sequence within the 1.3-kb fgl2 promoter region upstream from the transcription start site that was previously identified as necessary for N protein-induced gene transcription. We
demonstrated that the 331/325 HNF4 cis-element and its cognate transcription factor, HNF4
, are necessary for virus-induced
fgl2 gene transcription. In uninfected macrophages and
macrophages infected with MHV-2, an unidentified protein occupies the
HNF4 cis-element. Following stimulation with MHV-A59, it was shown by
electrophoretic mobility shift assay that HNF4 binds the HNF4 cis-element in the fgl2 promoter. We further report the
unprecedented presence of HNF4 in peritoneal macrophages.
Collectively, the results of this study define both viral and host
factors necessary for induction of fgl2 prothrombinase gene
transcription in MHV infection and may provide an explanation for the
hepatotrophic nature of MHV-induced fulminant hepatic failure.
*
This work was supported in part by Canadian Institutes for
Health and Research Grant MOP 37780.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.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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