Journal
CELL REPORTS
Volume 38, Issue 10, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.110434
Keywords
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Categories
Funding
- NIH/NIAID [R01AI134907, R01AI166668, R01AI155466, P01AI150585, R21AI126012, R21AI132479]
- UTMB/IHII [R01AI134907, UL1TR001439]
- DARPA [HR0011-19-2-0020]
- F. HoffmannLa Roche, Vir Biotechnology
- QCRG [U19AI135972]
- CRIPT/CEIRR contract [75N93019R00028]
- Sealy & Smith foundation [U19AI135972, T32AI007526, F31AI152422, T32AI060549, K12HD052023, P50AI150476, R01AI143292, P01AI063302]
- Kleberg foundation [U19AI135972, T32AI007526, F31AI152422, T32AI060549, K12HD052023, P50AI150476, R01AI143292, P01AI063302]
- John S. Dunn foundation [U19AI135972, T32AI007526, F31AI152422, T32AI060549, K12HD052023, P50AI150476, R01AI143292, P01AI063302]
- Amon G. Carter foundation [U19AI135972, T32AI007526, F31AI152422, T32AI060549, K12HD052023, P50AI150476, R01AI143292, P01AI063302]
- Gilson Longenbaugh foundation [U19AI135972, T32AI007526, F31AI152422, T32AI060549, K12HD052023, P50AI150476, R01AI143292, P01AI063302]
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This study identifies the RNA helicase DHX16 as a pattern recognition receptor (PRR) that partners with RIG-I for optimal activation of antiviral immunity requiring unanchored polyubiquitin (poly-Ub).
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.
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