Random mutagenesis defines a domain of Theiler's virus leader protein which is essential for antagonism of nucleocytoplasmic trafficking and of cytokine gene expression.
(2009) Journal of Virology — Vol. 83, n° 21, p. 11223-11232 (2009)
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- Abstract
- 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 TMEV capacity to establish persistent infection of the central nervous system. Mutants of the TMEV leader 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, thus called "Theilo domain". Mutations in this domain had the most dramatic impact on TMEV L protein activity. Like the zinc finger mutation, Theilo domain mutations affected all the tested activities of the L protein: interferon gene transcription and IRF-3 dimerization antagonism, alteration of nucleocytoplasmic trafficking, nucleoporin 98 (Nup98) 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 tested activities were affected by these mutations suggests the various leader protein functions are somehow coupled.
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Ricour, C., Borghese, F., Sorgeloos, F., Hato, S. V., van Kuppeveld, F. J. M., & Michiels, T. (2009). Random mutagenesis defines a domain of Theiler’s virus leader protein which is essential for antagonism of nucleocytoplasmic trafficking and of cytokine gene expression. Journal of Virology, 83(21), 11223-11232. https://doi.org/10.1128/JVI.00829-09 (Original work published 2009)