title: Measles virus C protein interferes with Beta interferon transcription in the nucleus.
abstract: Transcriptional induction of beta interferon (IFN-β) through pattern recognition receptors is a key event in the host defense against invading viruses. Infection of cells by paramyxoviruses, like measles virus (MV) (genus Morbillivirus), is sensed predominantly by the ubiquitous cytoplasmic helicase RIG-I, recognizing viral 5'-triphosphate RNAs, and to some degree by MDA5. While MDA5 activation is effectively prevented by the MV V protein, the viral mechanisms for inhibition of MDA5-independent induction of IFN-β remained obscure. Here, we identify the 186-amino-acid MV C protein, which shuttles between the nucleus and the cytoplasm, as a major viral inhibitor of IFN-β transcription in human cells. Activation of the transcription factor IRF3 by upstream kinases and nuclear import of activated IRF3 were not affected in the presence of C protein, suggesting a nuclear target. Notably, C proteins of wild-type MV isolates, which are poor IFN-β inducers, were found to comprise a canonical nuclear localization signal (NLS), whereas the NLSs of all vaccine strains, irrespective of their origins, were mutated. Site-directed mutagenesis of the C proteins from an MV wild-type isolate and from the vaccine virus strain Schwarz confirmed a correlation of nuclear localization and inhibition of IFN-β transcription. A functional NLS and efficient nuclear accumulation are therefore critical for MV C to retain its potential to downregulate IFN-β induction. We suggest that a defect in efficient nuclear import of C protein contributes to attenuation of MV vaccine strains.
authors.affiliation: Max von Pettenkofer-Institute and Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Konstantin M J
authors.initials: KM
authors.lastname: Sparrer
authors.forename: Christian K
authors.initials: CK
authors.lastname: Pfaller
authors.forename: Karl-Klaus
authors.initials: KK
authors.lastname: Conzelmann
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D008457:Measles / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D008459:Measles virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D021381:Protein Transport; D016415:Sequence Alignment; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D016899:Interferon-beta
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