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

• Published in: bioRxiv
• Main Authors: Woltz, Ryan, Schweibenz, Brandon, Tsutakawa, Susan E, Zhao, Chen, Ma, LiChung, Shurina, Ben, Hura, Gregory L, John, Rachael, Vorobiev, Sergey, Swapna, Gvt, Solotchi, Mihai, Tainer, John A, Krug, Robert M, Patel, Smita S, Montelione, Gaetano T
• Format: Journal Article
• Language: English
• Published: United States 24.01.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.09.25.559316

Influenza A and B viruses overcome the host antiviral response to cause a contagious and often severe human respiratory disease. Here, integrative structural biology and biochemistry studies on non-structural protein 1 of influenza B virus (NS1B) reveal a previously unrecognized viral mechanism for innate immune evasion. Conserved basic groups of its C-terminal domain (NS1B-CTD) bind 5'triphosphorylated double-stranded RNA (5'-ppp-dsRNA), the primary pathogen-associated feature that activates the host retinoic acid-inducible gene I protein (RIG-I) to initiate interferon synthesis and the cellular antiviral response. Like RIG-I, NS1B-CTD preferentially binds blunt-end 5'ppp-dsRNA. NS1B-CTD also competes with RIG-I for binding 5'ppp-dsRNA, and thus suppresses activation of RIG-I's ATPase activity. Although the NS1B N-terminal domain also binds dsRNA, it utilizes a different binding mode and lacks 5'ppp-dsRNA end preferences. In cells infected with wild-type influenza B virus, RIG-I activation is inhibited. In contrast, 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 R208A substitution it its CTD that eliminates its 5'ppp-dsRNA binding activity. These results reveal a novel mechanism in which NS1B binds 5'ppp-dsRNA to inhibit the RIG-I antiviral response during influenza B virus infection, and open the door to new avenues for antiviral drug discovery.