Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein

Céline Ricour, Sophie Delhaye, Stanleyson V. Hato, Tamara D. Olenyik, Bénédicte Michel, Frank J M van Kuppeveld, Kurt E Gustin, Thomas Michiels

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Theiler's murine encephalomyelitis virus (TMEV or Theiler's virus) is a neurotropic picornavirus that can persist lifelong in the central nervous system of infected mice, causing a chronic inflammatory demyelinating disease. The leader (L) protein of the virus is an important determinant of viral persistence and has been shown to inhibit transcription of type I interferon (IFN) genes and to cause nucleocytoplasmic redistribution of host proteins. In this study, it was shown that expression of the L protein shuts off synthesis of the reporter proteins green fluorescent protein and firefly luciferase, suggesting that it induces a global shut-off of host protein expression. The L protein did not inhibit transcription or translation of the reporter genes, but blocked cellular mRNA export from the nucleus. This activity correlated with the phosphorylation of nucleoporin 98 (Nup98), an essential component of the nuclear pore complex. In contrast, the data confirmed that the L protein inhibited IFN expression at the transcriptional level, and showed that transcription of other chemokine or cytokine genes was affected by the L protein. This transcriptional inhibition correlated with inhibition of interferon regulatory factor 3 (IRF-3) dimerization. Whether inhibition of IRF-3 dimerization and dysfunction of the nuclear pore complex are related phenomena remains an open question. In vivo, IFN antagonism appears to be an important role of the L protein early in infection, as a virus bearing a mutation in the zinc finger of the L protein replicated as efficiently as the wild-type virus in type I IFN receptor-deficient mice, but had impaired fitness in IFN-competent mice.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalJournal of General Virology
Volume90
Issue number1
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Interferon Regulatory Factor-3
Theilovirus
Dimerization
Messenger RNA
Proteins
Interferons
Nuclear Pore
Viruses
Interferon alpha-beta Receptor
Nuclear Pore Complex Proteins
Picornaviridae
Firefly Luciferases
Interferon Type I
Zinc Fingers
Demyelinating Diseases
Green Fluorescent Proteins
Reporter Genes
Chemokines
Genes
Central Nervous System

ASJC Scopus subject areas

  • Virology

Cite this

Ricour, C., Delhaye, S., Hato, S. V., Olenyik, T. D., Michel, B., van Kuppeveld, F. J. M., ... Michiels, T. (2009). Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein. Journal of General Virology, 90(1), 177-186. https://doi.org/10.1099/vir.0.005678-0

Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein. / Ricour, Céline; Delhaye, Sophie; Hato, Stanleyson V.; Olenyik, Tamara D.; Michel, Bénédicte; van Kuppeveld, Frank J M; Gustin, Kurt E; Michiels, Thomas.

In: Journal of General Virology, Vol. 90, No. 1, 2009, p. 177-186.

Research output: Contribution to journalArticle

Ricour, C, Delhaye, S, Hato, SV, Olenyik, TD, Michel, B, van Kuppeveld, FJM, Gustin, KE & Michiels, T 2009, 'Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein', Journal of General Virology, vol. 90, no. 1, pp. 177-186. https://doi.org/10.1099/vir.0.005678-0
Ricour, Céline ; Delhaye, Sophie ; Hato, Stanleyson V. ; Olenyik, Tamara D. ; Michel, Bénédicte ; van Kuppeveld, Frank J M ; Gustin, Kurt E ; Michiels, Thomas. / Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein. In: Journal of General Virology. 2009 ; Vol. 90, No. 1. pp. 177-186.
@article{b6b2aa526a4e49ac8fafa7358313f909,
title = "Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein",
abstract = "Theiler's murine encephalomyelitis virus (TMEV or Theiler's virus) is a neurotropic picornavirus that can persist lifelong in the central nervous system of infected mice, causing a chronic inflammatory demyelinating disease. The leader (L) protein of the virus is an important determinant of viral persistence and has been shown to inhibit transcription of type I interferon (IFN) genes and to cause nucleocytoplasmic redistribution of host proteins. In this study, it was shown that expression of the L protein shuts off synthesis of the reporter proteins green fluorescent protein and firefly luciferase, suggesting that it induces a global shut-off of host protein expression. The L protein did not inhibit transcription or translation of the reporter genes, but blocked cellular mRNA export from the nucleus. This activity correlated with the phosphorylation of nucleoporin 98 (Nup98), an essential component of the nuclear pore complex. In contrast, the data confirmed that the L protein inhibited IFN expression at the transcriptional level, and showed that transcription of other chemokine or cytokine genes was affected by the L protein. This transcriptional inhibition correlated with inhibition of interferon regulatory factor 3 (IRF-3) dimerization. Whether inhibition of IRF-3 dimerization and dysfunction of the nuclear pore complex are related phenomena remains an open question. In vivo, IFN antagonism appears to be an important role of the L protein early in infection, as a virus bearing a mutation in the zinc finger of the L protein replicated as efficiently as the wild-type virus in type I IFN receptor-deficient mice, but had impaired fitness in IFN-competent mice.",
author = "C{\'e}line Ricour and Sophie Delhaye and Hato, {Stanleyson V.} and Olenyik, {Tamara D.} and B{\'e}n{\'e}dicte Michel and {van Kuppeveld}, {Frank J M} and Gustin, {Kurt E} and Thomas Michiels",
year = "2009",
doi = "10.1099/vir.0.005678-0",
language = "English (US)",
volume = "90",
pages = "177--186",
journal = "Journal of General Virology",
issn = "0022-1317",
publisher = "Society for General Microbiology",
number = "1",

}

TY - JOUR

T1 - Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein

AU - Ricour, Céline

AU - Delhaye, Sophie

AU - Hato, Stanleyson V.

AU - Olenyik, Tamara D.

AU - Michel, Bénédicte

AU - van Kuppeveld, Frank J M

AU - Gustin, Kurt E

AU - Michiels, Thomas

PY - 2009

Y1 - 2009

N2 - Theiler's murine encephalomyelitis virus (TMEV or Theiler's virus) is a neurotropic picornavirus that can persist lifelong in the central nervous system of infected mice, causing a chronic inflammatory demyelinating disease. The leader (L) protein of the virus is an important determinant of viral persistence and has been shown to inhibit transcription of type I interferon (IFN) genes and to cause nucleocytoplasmic redistribution of host proteins. In this study, it was shown that expression of the L protein shuts off synthesis of the reporter proteins green fluorescent protein and firefly luciferase, suggesting that it induces a global shut-off of host protein expression. The L protein did not inhibit transcription or translation of the reporter genes, but blocked cellular mRNA export from the nucleus. This activity correlated with the phosphorylation of nucleoporin 98 (Nup98), an essential component of the nuclear pore complex. In contrast, the data confirmed that the L protein inhibited IFN expression at the transcriptional level, and showed that transcription of other chemokine or cytokine genes was affected by the L protein. This transcriptional inhibition correlated with inhibition of interferon regulatory factor 3 (IRF-3) dimerization. Whether inhibition of IRF-3 dimerization and dysfunction of the nuclear pore complex are related phenomena remains an open question. In vivo, IFN antagonism appears to be an important role of the L protein early in infection, as a virus bearing a mutation in the zinc finger of the L protein replicated as efficiently as the wild-type virus in type I IFN receptor-deficient mice, but had impaired fitness in IFN-competent mice.

AB - Theiler's murine encephalomyelitis virus (TMEV or Theiler's virus) is a neurotropic picornavirus that can persist lifelong in the central nervous system of infected mice, causing a chronic inflammatory demyelinating disease. The leader (L) protein of the virus is an important determinant of viral persistence and has been shown to inhibit transcription of type I interferon (IFN) genes and to cause nucleocytoplasmic redistribution of host proteins. In this study, it was shown that expression of the L protein shuts off synthesis of the reporter proteins green fluorescent protein and firefly luciferase, suggesting that it induces a global shut-off of host protein expression. The L protein did not inhibit transcription or translation of the reporter genes, but blocked cellular mRNA export from the nucleus. This activity correlated with the phosphorylation of nucleoporin 98 (Nup98), an essential component of the nuclear pore complex. In contrast, the data confirmed that the L protein inhibited IFN expression at the transcriptional level, and showed that transcription of other chemokine or cytokine genes was affected by the L protein. This transcriptional inhibition correlated with inhibition of interferon regulatory factor 3 (IRF-3) dimerization. Whether inhibition of IRF-3 dimerization and dysfunction of the nuclear pore complex are related phenomena remains an open question. In vivo, IFN antagonism appears to be an important role of the L protein early in infection, as a virus bearing a mutation in the zinc finger of the L protein replicated as efficiently as the wild-type virus in type I IFN receptor-deficient mice, but had impaired fitness in IFN-competent mice.

UR - http://www.scopus.com/inward/record.url?scp=59849121682&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59849121682&partnerID=8YFLogxK

U2 - 10.1099/vir.0.005678-0

DO - 10.1099/vir.0.005678-0

M3 - Article

C2 - 19088287

AN - SCOPUS:59849121682

VL - 90

SP - 177

EP - 186

JO - Journal of General Virology

JF - Journal of General Virology

SN - 0022-1317

IS - 1

ER -