Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4 alpha
- PMID: 12594208
- DOI: 10.1074/jbc.M212806200
Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4 alpha
Abstract
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 -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, HNF4alpha, 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 HNF4alpha binds the HNF4 cis-element in the fgl2 promoter. We further report the unprecedented presence of HNF4alpha 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.
Similar articles
-
FGL1 and FGL2: emerging regulators of liver health and disease.Biomark Res. 2024 May 31;12(1):53. doi: 10.1186/s40364-024-00601-0. Biomark Res. 2024. PMID: 38816776 Free PMC article. Review.
-
[The study of cis-element HNF4 in the regulation of mfg12 prothrombinase/fibroleukin gene expression in response to nucleocapsid protein of MHV-3].Zhonghua Yi Xue Za Zhi. 2003 Apr 25;83(8):678-83. Zhonghua Yi Xue Za Zhi. 2003. PMID: 12887828 Chinese.
-
The nucleocapsid protein of murine hepatitis virus type 3 induces transcription of the novel fgl2 prothrombinase gene.J Biol Chem. 1999 Apr 9;274(15):9930-6. doi: 10.1074/jbc.274.15.9930. J Biol Chem. 1999. PMID: 10187767
-
Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression.Front Immunol. 2018 Dec 13;9:2935. doi: 10.3389/fimmu.2018.02935. eCollection 2018. Front Immunol. 2018. PMID: 30619295 Free PMC article.
-
Murine coronavirus neuropathogenesis: determinants of virulence.J Neurovirol. 2010 Nov;16(6):427-34. doi: 10.3109/13550284.2010.529238. Epub 2010 Nov 12. J Neurovirol. 2010. PMID: 21073281 Free PMC article. Review.
Cited by
-
FGL1 and FGL2: emerging regulators of liver health and disease.Biomark Res. 2024 May 31;12(1):53. doi: 10.1186/s40364-024-00601-0. Biomark Res. 2024. PMID: 38816776 Free PMC article. Review.
-
Multi-Organ Histopathological Changes in a Mouse Hepatitis Virus Model of COVID-19.Viruses. 2021 Aug 27;13(9):1703. doi: 10.3390/v13091703. Viruses. 2021. PMID: 34578284 Free PMC article.
-
Human genetic basis of fulminant viral hepatitis.Hum Genet. 2020 Jun;139(6-7):877-884. doi: 10.1007/s00439-020-02166-y. Epub 2020 Apr 13. Hum Genet. 2020. PMID: 32285199 Free PMC article. Review.
-
The Role of Fibrinogen-Like Protein 2 on Immunosuppression and Malignant Progression in Glioma.J Natl Cancer Inst. 2019 Mar 1;111(3):292-300. doi: 10.1093/jnci/djy107. J Natl Cancer Inst. 2019. PMID: 29947810 Free PMC article.
-
The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis.PLoS Pathog. 2015 Sep 14;11(9):e1005155. doi: 10.1371/journal.ppat.1005155. eCollection 2015 Sep. PLoS Pathog. 2015. PMID: 26367131 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous