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Journal of Virology, November 2009, p. 11223-11232, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00829-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Random Mutagenesis Defines a Domain of Theiler's Virus Leader Protein That Is Essential for Antagonism of Nucleocytoplasmic Trafficking and Cytokine Gene Expression{triangledown}

Céline Ricour,1 Fabian Borghese,1 Frédéric Sorgeloos,1 Stanleyson V. Hato,2 Frank J. M. van Kuppeveld,2 and Thomas Michiels1*

Université catholique de Louvain, de Duve Institute, Brussels, Belgium,1 Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands2

Received 23 April 2009/ Accepted 5 August 2009

The leader protein of cardioviruses, Theiler's murine encephalomyelitis virus (TMEV) and encephalomyocarditis virus (EMCV), is a multifunctional protein known to antagonize type I interferon expression and to interfere with nucleocytoplasmic trafficking of host proteins and mRNA. This protein plays an important role in the capacity of TMEV to establish persistent infection of the central nervous system. Mutant forms of the TMEV leader protein were generated by random mutagenesis and selected after retroviral transduction on the basis of the loss of the highly toxic nature of this protein. Selected mutations define a short C-terminal domain of the leader conserved in TMEV and Saffold virus but lacking in the EMCV leader and thus called the Theilo domain. Mutations in this domain had a dramatic impact on TMEV L protein activity. Like the zinc finger mutation, Theilo domain mutations affected all of the activities of the L protein tested: interferon gene transcription and IRF-3 dimerization antagonism, alteration of nucleocytoplasmic trafficking, nucleoporin 98 hyperphosphorylation, and viral persistence in vivo. This suggests that the Zn finger and the Theilo domain of the protein cooperate for function. Moreover, the fact that all of the activities tested were affected by these mutations suggests that the various leader protein functions are somehow coupled.

* Corresponding author. Mailing address: Université catholique de Louvain, de Duve Institute, MIPA-VIRO 74-49, 74, Avenue Hippocrate, B-1200, Brussels, Belgium. Phone: 32 2 764 74 29. Fax: 32 2 764 74 95. E-mail: thomas.michiels{at}uclouvain.be

{triangledown} Published ahead of print on 26 August 2009.

Journal of Virology, November 2009, p. 11223-11232, Vol. 83, No. 21
0022-538X/09/$08.00+0     doi:10.1128/JVI.00829-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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