Mechanisms of Protein Kinase PKR-Mediated Amplification of Beta Interferon Induction by C Protein-Deficient Measles Virus

The measles virus P gene products V and C antagonize the host interferon (IFN) response, blocking both IFN signaling and production. Using Moraten vaccine strain-derived measles virus and isogenic mutants deficient for either V or C protein production (V-ko and C-ko, respectively), we observed that the C-ko virus was a potent inducer of IFN-beta, while induction by V-ko virus was an order of magnitude lower than that by the C-ko virus. The parental recombinant Moraten virus did not significantly induce IFN-beta. The enhanced IFN-inducing capacity of the C-ko virus correlated with an enhanced activation of IFN regulatory factor 3 (IRF-3), NF-kappa B, and ATF-2 in C-ko-infected compared to V-ko or parental virus-infected cells. Furthermore, protein kinase PKR and mitochondrial adapter IPS-1 were required for maximal C-ko-mediated IFN-beta induction, which correlated with the PKR-mediated enhancement of mitogen-activated protein kinase and NF-kappa B activation. Our results reveal multiple consequences of C protein expression and document an important function for PKR as an enhancer of IFN-beta induction during measles virus infection.