@article{4747bd5661c14821a1c2ada89b0e2903,
title = "The RNA helicase DHX16 recognizes specific viral RNA to trigger RIG-I-dependent innate antiviral immunity",
abstract = "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.",
keywords = "DHX16, RIG-I, SARS-CoV-2, TRIM6, influenza A virus, innate immunity, splicing, tripartite motif (TRIM) protein, type I interferon, unanchored ubiquitin",
author = "Adam Hage and Preeti Bharaj and {van Tol}, Sarah and Giraldo, {Maria I.} and Maria Gonzalez-Orozco and Valerdi, {Karl M.} and Warren, {Abbey N.} and Leopoldo Aguilera-Aguirre and Xuping Xie and Widen, {Steven G.} and Moulton, {Hong M.} and Benhur Lee and Johnson, {Jeffrey R.} and Krogan, {Nevan J.} and Adolfo Garc{\'i}a-Sastre and Shi, {Pei Yong} and Freiberg, {Alexander N.} and {Rajsbaum Gorodezky}, Ricardo",
note = "Funding Information: This work was supported by NIH / NIAID grants R01AI134907 , R01AI166668 , R01AI155466 , P01AI150585 , R21AI126012 , R21AI132479 , and UTMB /IHII awarded to R.R. R01AI134907 , UL1TR001439 , and awards from Sealy & Smith, Kleberg, John S. Dunn, Amon G. Carter, Gilson Longenbaugh, and Summerfield Robert foundations awarded to P.-Y.S. T32AI007526 awarded to A.H. F31AI152422 and T32AI060549 awarded to S.v.T. K12HD052023 awarded to M.I.G. P50AI150476 , U19AI135972 , R01AI143292 , P01AI063302 , and awards from DARPA #HR0011-19-2-0020 , F. Hoffmann-La Roche , Vir Biotechnology , and QCRG donors to N.J.K. U19AI135972 and CRIPT / CEIRR contract #75N93019R00028 to A.G.-S. We thank Maxim Ivannikov (UTMB Imaging Core) for assistance with confocal microscopy and Linsey Yeager for editing of the manuscript. Funding Information: This work was supported by NIH/NIAID grants R01AI134907, R01AI166668, R01AI155466, P01AI150585, R21AI126012, R21AI132479, and UTMB/IHII awarded to R.R. R01AI134907, UL1TR001439, and awards from Sealy & Smith, Kleberg, John S. Dunn, Amon G. Carter, Gilson Longenbaugh, and Summerfield Robert foundations awarded to P.-Y.S. T32AI007526 awarded to A.H. F31AI152422 and T32AI060549 awarded to S.v.T. K12HD052023 awarded to M.I.G. P50AI150476, U19AI135972, R01AI143292, P01AI063302, and awards from DARPA #HR0011-19-2-0020, F. Hoffmann-La Roche, Vir Biotechnology, and QCRG donors to N.J.K. U19AI135972 and CRIPT/CEIRR contract #75N93019R00028 to A.G.-S. We thank Maxim Ivannikov (UTMB Imaging Core) for assistance with confocal microscopy and Linsey Yeager for editing of the manuscript. A.H. performed all aspects of this study. P.B. R.R. S.v.T. M.I.G. M.G.-O. K.M.V. A.N.W. and L.A.-A. performed experiments. X.X. B.L. P.-Y.S. A.N.F. and A.G.-S. provided critical reagents and technical advice. S.G.W. performed and analyzed NGS and MISO. H.M.M. designed and synthesized PPMOs. J.R.J. and N.J.K. performed and analyzed MS. A.H. and R.R. organized the study and prepared the manuscript. All authors read the manuscript and provided comments. The Garc{\'i}a-Sastre laboratory received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7 Hills Pharma, PharmaMar, ImmunityBio, Accurius, nanoComposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, and Merck. The Krogan laboratory received research support from Vir Biotechnology and F. Hoffmann-La Roche. All declarations of interest are outside of the reported work. All remaining authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = mar,
day = "8",
doi = "10.1016/j.celrep.2022.110434",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}