Journal article
Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export
The Journal of cell biology, Vol.196(3), pp.315-326
02/06/2012
DOI: 10.1083/jcb.201107058
PMCID: PMC3275370
PMID: 22312003
Abstract
The NS1 protein of influenza virus is a major virulence factor essential for virus replication, as it redirects the host cell to promote viral protein expression. NS1 inhibits cellular messenger ribonucleic acid (mRNA) processing and export, down-regulating host gene expression and enhancing viral gene expression. We report in this paper the identification of a nontoxic quinoline carboxylic acid that reverts the inhibition of mRNA nuclear export by NS1, in the absence or presence of the virus. This quinoline carboxylic acid directly inhibited dihydroorotate dehydrogenase (DHODH), a host enzyme required for de novo pyrimidine biosynthesis, and partially reduced pyrimidine levels. This effect induced NXF1 expression, which promoted mRNA nuclear export in the presence of NS1. The release of NS1-mediated mRNA export block by DHODH inhibition also occurred in the presence of vesicular stomatitis virus M (matrix) protein, another viral inhibitor of mRNA export. This reversal of mRNA export block allowed expression of antiviral factors. Thus, pyrimidines play a necessary role in the inhibition of mRNA nuclear export by virulence factors.
Details
- Title: Subtitle
- Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export
- Creators
- Liang Zhang - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Priyabrata Das - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Mirco Schmolke - Department of Microbiology, Department of Medicine, Division of Infectious Diseases, and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029Balaji Manicassamy - Department of Microbiology, Department of Medicine, Division of Infectious Diseases, and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029Yaming Wang - Department of Pathology, New York University School of Medicine, New York, NY 10016Xiaoyi Deng - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Ling Cai - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Benjamin P Tu - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Christian V Forst - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Michael G Roth - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390David E Levy - Department of Pathology, New York University School of Medicine, New York, NY 10016Adolfo García-Sastre - Department of Microbiology, Department of Medicine, Division of Infectious Diseases, and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, Department of Microbiology, Department of Medicine, Division of Infectious Diseases, and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029, Department of Microbiology, Department of Medicine, Division of Infectious Diseases, and Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029Jef de Brabander - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Margaret A Phillips - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390Beatriz M.A Fontoura - Department of Cell Biology, Department of Biochemistry, Department of Pharmacology, and Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390
- Resource Type
- Journal article
- Publication Details
- The Journal of cell biology, Vol.196(3), pp.315-326
- DOI
- 10.1083/jcb.201107058
- PMID
- 22312003
- PMCID
- PMC3275370
- ISSN
- 0021-9525
- eISSN
- 1540-8140
- Language
- English
- Date published
- 02/06/2012
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083288902771
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