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

Abstract

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‐α‐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‐α/β receptor subunit (IFNAR)2 and inhibits IFN‐α‐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.