Activation of the Beta Interferon Promoter by Unnatural Sendai Virus Infection Requires RIG-I and Is Inhibited by Viral C Proteins

This study investigated how unnatural infections with Sendai virus activate the host beta interferon (IFN-β) response and examined the respective roles of the viral C and V proteins in suppressing innate antiviral signaling. Using two engineered Sendai virus infection systems, one involving defective interfering (DI-H4) genomes that overproduce 5′-triphosphorylated trailer RNAs and another generating intracellular GFP-derived double-stranded RNA (dsRNA), the authors demonstrated that activation of the IFN-β promoter in mouse embryonic fibroblasts depended predominantly on the cytoplasmic RNA sensor RIG-I rather than mda-5. The study showed that both 5′-triphosphorylated single-stranded RNAs and dsRNAs acted as potent pathogen-associated molecular patterns capable of inducing IFN-β signaling through the RIG-I pathway. The authors further established that the Sendai virus C protein was the principal antagonist of RIG-I-mediated interferon induction, whereas the V protein played a comparatively limited role. Overexpression of the C protein strongly inhibited IFN-β activation induced by defective interfering virus infection, dsRNA formation, transfected poly(I-C), and synthetic 5′-triphosphorylated RNAs, with inhibitory activity comparable to dominant-negative RIG-I constructs and influenza virus NS1 protein. In contrast, the V protein only partially suppressed signaling and was ineffective against several dsRNA-mediated responses. Functional analyses using recombinant viruses lacking either the C or V protein confirmed that loss of the C protein resulted in strong enhancement of IFN-β activation and synergistic stimulation of antiviral signaling following RNA transfection, whereas V-deficient virus largely retained wild-type suppressive activity. The study also identified the C-terminal C24–204/Y1 interaction domain of the C protein as the major determinant responsible for inhibition of RIG-I-dependent signaling. Overall, this work demonstrated that Sendai virus employs the C protein as a major innate immune evasion factor to counteract RIG-I-mediated antiviral responses triggered by viral pppRNAs and dsRNAs, thereby providing important mechanistic insight into paramyxovirus interferon antagonism and host–virus interactions.
(TMR)