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

Cell Reports (Mar 2022)

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

Affiliations

Adam Hage: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Preeti Bharaj: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Sarah van Tol: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Maria I. Giraldo: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Maria Gonzalez-Orozco: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Karl M. Valerdi: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Abbey N. Warren: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
Leopoldo Aguilera-Aguirre: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
Xuping Xie: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
Steven G. Widen: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
Hong M. Moulton: Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
Benhur Lee: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Jeffrey R. Johnson: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Nevan J. Krogan: Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI) COVID-19 Research Group (QCRG), University of California at San Francisco, San Francisco, CA 94158, USA; Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA 94158, USA
Adolfo García-Sastre: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Pei-Yong Shi: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
Alexander N. Freiberg: Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
Ricardo Rajsbaum: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Corresponding author

Journal volume & issue: Vol. 38, no. 10
p. 110434

Abstract

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Summary: 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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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