The V protein of Sendai virus (SeV) suppresses innate immunity, resulting in enhancement of viral growth in mouse lungs and viral pathogenicity. The innate immunity restricted by the V protein is induced through activation of interferon regulatory factor 3 (IRF3). The V protein has been shown to interact with melanoma differentiation-associated gene 5 (MDA5) and to inhibit beta interferon production. In the present study, we infected MDA5-knockout mice with V-deficient SeV and found that MDA5 was largely unrelated to the innate immunity that the V protein suppresses in vivo. We therefore investigated the target of the SeV V protein. We previously reported interaction of the V protein with IRF3. Here we extended the observation and showed that the V protein appeared to inhibit translocation of IRF3 into the nucleus. We also found that the V protein inhibited IRF3 activation when induced by a constitutive active form of IRF3. The V proteins of measles virus and Newcastle disease virus inhibited IRF3 transcriptional activation, as did the V protein of SeV, while the V proteins of mumps virus and Nipah virus did not, and inhibition by these proteins correlated with interaction of each V protein with IRF3. These results indicate that IRF3 is important as an alternative target of paramyxovirus V proteins. The family Paramyxoviridae includes numerous human and animal pathogens such as measles virus (MeV), mumps virus (MuV), respiratory syncytial virus, canine distemper virus, Newcastle disease virus (NDV), Nipah virus (NiV), and Hendra virus. Paramyxoviruses possess accessory proteins that are not essential for minimal virus growth but are essential for efficient and pathogenic infection. Sendai virus (SeV), which belongs to the family Paramyxoviridae, is a respiratory tract pathogen of rodents and has accessory proteins C and V. The SeV genome, which is approximately 15.4 kb, comprises six genes, N, P, M, F, HN, and L, and the genes individually encode one polypeptide. The P gene exceptionally encodes the C and V proteins as well as the P protein (27, 32).The C proteins, C=, C, Y1, and Y2, are synthesized from the colinear transcript of the P gene in an open reading frame (ORF) shifted from that of the P protein by alternative translational starts and a common stop codon. The C proteins have multiple functions, including interruption of the Jak/Stat pathway to inhibit interferon (IFN)-responsive gene activation (8, 10), inhibition of apoptosis (13, 26), viral RNA synthesis regulation (2,5,6,14,45), and assistance with virus particle formation (15,38,41). Inhibition of apoptosis may be linked to proper regulation of viral RNA synthesis by viral polymerase with the assistance of the C protein (13, 43).The V protein is synthesized from an additional mRNA, which is generated from the P gene by inserting a pseudotemplated G residue at the specific editing site in the middle of the gene (46, 47). Consequently, the P and V proteins share the same 317 residues at the amino terminus (P/V common region), and the V protein has a...
One of the accessory proteins of Sendai virus (SeV), C, translated from an alternate reading frame of P/V mRNA has been shown to function at multiple stages of infection in cell cultures as well as in mice. C protein has been reported to counteract signal transduction by interferon (IFN), inhibit apoptosis induced by the infection, enhance the efficiency of budding of viral particles, and regulate the polarity of viral genome-length RNA synthesis to maximize production of infectious particles. In this study, we have generated a series of SeV recombinants containing substitutions of highly conserved, charged residues within the C protein, and characterized them together with previously-reported C′/C(−), 4C(−), and F170S recombinant viruses in infected cell cultures in terms of viral replication, cytopathogenicity, and antagonizing effects on host innate immunity. Unexpectedly, the amino acid substitutions had no or minimal effect on viral growth and viral RNA synthesis. However, all the substitutions of charged amino acids resulted in the loss of a counteracting effect against the establishment of an IFN-α-mediated anti-viral state. Infection by the virus (Cm2′) containing mutations at K77 and D80 induced significant IFN-β production, severe cytopathic effects, and detectable amounts of viral dsRNA production. In addition to the Cm2′ virus, the virus containing mutations at E114 and E115 did not inhibit the poly(I:C)-triggered translocation of cellular IRF-3 to the nucleus. These results suggest that the C protein play important roles in viral escape from induction of IFN-β and cell death triggered by infection by means of counteracting the pathway leading to activation of IRF-3 as well as of minimizing viral dsRNA production.
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