Measles Virus C Protein Interferes with Beta Interferon Transcription in the Nucleus

Abstract

Transcriptional induction of beta interferon (IFN-␤) 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-␤ 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-␤ 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-␤ 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-␤ transcription. A functional NLS and efficient nuclear accumulation are therefore critical for MV C to retain its potential to downregulate IFN-␤ induction. We suggest that a defect in efficient nuclear import of C protein contributes to attenuation of MV vaccine strains.A ntiviral host defense relies on rapid recognition of invading viruses by pattern recognition receptors (PRRs), like the ubiquitous cytoplasmic RIG-I-like receptors (RLR), which include RIG-I, MDA5, and LGP-2, and a number of Toll-like receptors (TLR) operating mainly in specialized immune cells. Virus sensing by these receptors leads to activation of the transcription factors interferon regulatory factor 3 (IRF3) and IRF7 and nuclear factor kappa B (NF-B), which orchestrate transcriptional activation of type I interferons (alpha interferon [IFN-␣], IFN-␤, IFN-, and IFN-) and of proinflammatory cytokines (30, 43). Secreted early IFN-␤ alerts noninfected cells via binding to the IFN-␣ receptor (IFNAR) and activation of JAK/STAT signaling (50), which results in the induction of numerous IFN-stimulated genes (ISG). The established antiviral state limits further spread of the virus. As illustrated in the past decade, most viruses utilize multiple mechanisms to limit both the induction of and the response to type I IFN in order to be able to establish an infection (19,55,67). In the subfamily Paramyxovirinae, these functions are taken over by the diverse products of the phosphoprotein (P) gene (for a comprehensive review, see reference 22).Measles virus (MV) is a member of the genus Morbillivirus within the subfamily Paramyxovirinae and, in spite of the availability of safe live attenuated vaccines, remains a major cause of childhood mortality in developing countries (6...

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