Recognition of the measles virus nucleocapsid as a mechanism of IRF-3 activation.
The mechanisms of cellular recognition for virus infection remain poorly understood despite the wealth of information regarding the signaling events and transcriptional responses that ensue. Host cells respond to viral infection through the activation of multiple signaling cascades, including the activation of NF-kappaB, c-Jun/ATF-2 (AP-1), and the interferon regulatory factors (IRFs). Although viral products such as double-stranded RNA (dsRNA) and the processes of viral binding and fusion have been implicated in the activation of NF-kappaB and AP-1, the mechanism(s) of IRF-1, IRF-3, and IRF-7 activation has yet to be fully elucidated. Using recombinant measles virus (MeV) constructs, we now demonstrate that phosphorylation-dependent IRF-3 activation represents a novel cellular detection system that recognizes the MeV nucleocapsid structure. At low multiplicities of infection, IRF-3 activation is dependent on viral transcription, since UV cross-linking and a deficient MeV containing a truncated polymerase L gene failed to induce IRF-3 phosphorylation. Expression of the MeV nucleocapsid (N) protein, without the requirement for any additional viral proteins or the generation of dsRNA, was sufficient for IRF-3 activation. In addition, the nucleocapsid protein was found to associate with both IRF-3 and the IRF-3 virus-activated kinase, suggesting that it may aid in the colocalization of the kinase and the substrate. Altogether, this study suggests that IRF-3 recognizes nucleocapsid structures during the course of an MeV infection and triggers the induction of interferon production.
tenOever
Benjamin R
BR
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada H3T 1E2.
Servant
Marc J
MJ
Grandvaux
Nathalie
N
Lin
Rongtuan
R
Hiscott
John
J
D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D008457:Measles / Q000276:immunology* / Q000821:virology; D008459:Measles virus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D008969:Molecular Sequence Data; D019251:Nucleocapsid / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D014157:Transcription Factors