The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity

Adam Hage, Preeti Bharaj, Sarah van Tol, Maria I. Giraldo, Maria Gonzalez-Orozco, Karl M. Valerdi, Abbey N. Warren, Leopoldo Aguilera-Aguirre, Xuping Xie, Steven G. Widen, Hong M. Moulton, Benhur Lee, Jeffrey R. Johnson, Nevan J. Krogan, Adolfo García-Sastre, Pei Yong Shi, Alexander N. Freiberg, Ricardo Rajsbaum

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish
Article number110434
JournalCell Reports
Issue number10
StatePublished - 8 Mar 2022


  • DHX16
  • RIG-I
  • SARS-CoV-2
  • TRIM6
  • influenza A virus
  • innate immunity
  • splicing
  • tripartite motif (TRIM) protein
  • type I interferon
  • unanchored ubiquitin


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