The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production.
Theiler's virus is a picornavirus responsible for a persistent infection of the central nervous system of the mouse, leading to a chronic demyelinating disease considered to be a model for multiple sclerosis. The leader (L) protein encoded by Theiler's virus is a 76-amino-acid-long peptide containing a zinc-binding motif. This motif is conserved in the L proteins of all cardioviruses, including encephalomyocarditis virus. The L protein of Theiler's virus was suggested to interfere with the alpha/beta interferon (IFN-alpha/beta) response (W.-P. Kong, G. D. Ghadge, and R. P. Roos, Proc. Natl. Acad. Sci. USA 91:1796-1800, 1994). We show that expression of the L protein indeed inhibits the production of alpha/beta interferon by infected L929 cells. The L protein specifically inhibits the transcription of the IFN-alpha4 and IFN-beta genes, which are known to be activated early in response to viral infection. Mutation of the zinc finger was sufficient to block the anti-interferon activity, outlining the importance of this motif in the L protein function. In agreement with the anti-interferon role of the L protein, a virus bearing a mutation in the zinc-binding motif was dramatically impaired in its ability to persist in the central nervous system of SJL/J mice.
van Pesch
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Christian de Duve Institute of Cellular Pathology, University of Louvain, B-1200 Brussels, Belgium.
van Eyll
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Michiels
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D016475:3T3 Cells; D000818:Animals; D018188:Cardiovirus Infections / Q000821:virology; D004268:DNA-Binding Proteins / Q000172:deficiency; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D007739:L Cells; D051379:Mice; D050794:STAT1 Transcription Factor; D017945:Theilovirus / Q000472:pathogenicity / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency; D014158:Transcription, Genetic / Q000187:drug effects*; D014764:Viral Proteins / Q000378:metabolism / Q000494:pharmacology*; D014779:Virus Replication
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014764:Viral Proteins; D016899:Interferon-beta