The NS1 protein of influenza B virus binds 5’-triphosphorylated dsRNA to suppress RIG-I activation and the antiviral innate immune response

SUMMARY

Innate immune evasion, which allows viruses to escape cellular detection, remains enigmatic. The NS1 protein of influenza B virus (NS1B) suppresses the host innate immune response to infection. Here, integrative structural biology studies revealed previously unrecognized blunt-end dsRNA binding by the NS1B C-terminal domain (NS1B-CTD), in which conserved basic groups interact with 5’-triphosphorylated double-stranded RNA (5’ppp-dsRNA), analogous to complexes formed by retinoic acid-inducible gene I (RIG-I). NS1B-CTD preferentially binds 5’ppp-dsRNA, the primary pathogen-associated feature that activates RIG-I. NS1B-CTD competition with RIG-I for 5’ppp-dsRNA suppresses activation of RIG-I’s ATPase activity that otherwise initiates interferon synthesis. The NS1B N-terminal RNA-binding domain lacks such 5’ppp-dsRNA end preferences. In cells infected with influenza B virus RIG-I activation is inhibited. However, RIG-I activation and the resulting phosphorylation of transcription factor IRF-3 are not inhibited in cells infected with a mutant virus encoding NS1B with a CTD R208A substitution that eliminates 5’ppp-dsRNA binding. We conclude that NS1B binds 5’ppp-dsRNA to inhibit the RIG-I innate immune response during influenza B virus infection.