Type I interferons (IFN-I) are essential to establish antiviral innate immunity. Unanchored (or free) polyubiquitin (poly-Ub) has been shown to regulate IFN-I responses. However, few unanchored poly-Ub interactors are known. To identify factors regulated by unanchored poly-Ub in a physiological setting, we developed an approach to isolate unanchored poly-Ub from lung tissue. We identified the RNA helicase DHX16 as a potential pattern recognition receptor (PRR). Silencing of DHX16 in cells and in vivo diminished IFN-I responses against influenza virus. These effects extended to members of other virus families, including Zika and SARS-CoV-2. DHX16-dependent IFN-I production requires RIG-I and unanchored K48-poly-Ub synthesized by the E3-Ub ligase TRIM6. DHX16 recognizes a signal in influenza RNA segments that undergo splicing and requires its RNA helicase motif for direct, high-affinity interactions with specific viral RNAs. Our study establishes DHX16 as a PRR that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored poly-Ub. Graphical abstract Virus recognition triggers antiviral innate immunity. Hage et al. identify the RNA helicase DHX16 as a pattern recognition receptor. DHX16 recognizes splicing signals contained in influenza A vRNA leading to efficient RIG-I-mediated antiviral responses, which are regulated by TRIM6 and unanchored polyubiquitin. DHX16 senses infection by other viruses including SARS-CoV-2.
【저자키워드】 SARS-CoV-2, Innate immunity, influenza A virus, type I interferon, RIG-I, splicing, unanchored ubiquitin, tripartite motif (TRIM) protein, DHX16, TRIM6,