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Scientific article
English

Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export

Contributors

Zhang, Liang; Das, Priyabrata; Schmolke, Mirco; Manicassamy, Balaji; Wang, Yaming; Deng, Xiaoyi; Cai, Ling; Tu, Benjamin P; Forst, Christian V; Roth, Michael G; Levy, David E; García-Sastre, Adolfo; de Brabander, Jef; Phillips, Margaret A; Fontoura, Beatriz M A

Published in

The Journal of cell biology, vol. 196, no. 3, p. 315-326

Publication date

2012

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.

Keywords

  • Active Transport, Cell Nucleus/physiology
  • Animals
  • Cell Nucleus/metabolism
  • Cells, Cultured
  • Dogs
  • Orthomyxoviridae/genetics/metabolism
  • Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors/metabolism
  • Pyrimidines/biosynthesis
  • RNA, Messenger/metabolism
  • RNA, Viral/metabolism
  • Viral Matrix Proteins/chemistry/metabolism
  • Viral Nonstructural Proteins/genetics/metabolism
  • Virulence
  • Virulence Factors/metabolism

UNIGE affiliation entities

Not a UNIGE publication

Citation (ISO format)

ZHANG, Liang et al. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. In: The Journal of cell biology, 2012, vol. 196, n° 3, p. 315–326. doi: 10.1083/jcb.201107058

Main files (1)

Article (Published version)

Identifiers

Journal ISSN

0021-9525
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Technical informations

Creation

22/09/2015 15:49:00

First validation

22/09/2015 15:49:00

Update

14/03/2023 23:50:59

Status update

14/03/2023 23:50:58

Last indexation

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