Respirovirus C protein inhibits activation of type I interferon receptor-associated kinases to block JAK-STAT signaling

Respirovirus C protein blocks the type I interferon (IFN)-stimulated activation of the JAK-STAT pathway. It has been reported that C protein inhibits IFN-alpha-stimulated tyrosine phosphorylation of STATs, but the underlying mechanism is poorly understood. Here, we show that the C protein of Sendai virus (SeV), a member of the Respirovirus genus, binds to the IFN receptor subunit IFN-alpha/beta receptor subunit (IFNAR)2 and inhibits IFN-alpha-stimulated tyrosine phosphorylation of the upstream receptor-associated kinases, JAK1 and TYK2. Analysis of various SeV C mutant (Cm) proteins demonstrates the importance of the inhibitory effect on receptor-associated kinase phosphorylation for blockade of JAK-STAT signaling. Furthermore, this inhibitory effect and the IFNAR2 binding capacity are observed for all the respirovirus C proteins examined. Our results suggest that respirovirus C protein inhibits activation of the receptor-associated kinases JAK1 and TYK2 possibly through interaction with IFNAR2.