Abstract
The innate immune system is equipped with many molecular sensors for microbial DNA/RNA to quickly mount antimicrobial host immune responses. In this paper, we identified DHX9, a DExDc helicase family member, as an important viral dsRNA sensor in myeloid dendritic cells (mDCs). Knockdown of DHX9 expression by small heteroduplex RNA dramatically blocked the ability of mDCs to produce IFN-α/β and proinflammatory cytokines in response to polyinosine-polycytidylic acid, influenza A, and reovirus. DHX9 could specifically bind polyinosine-polycytidylic acid via its double-strand RNA binding motifs. DHX9 interacted with IPS-1 via the HelicC-HA2-DUF and CARD domains of DHX9 and IPS-1, respectively. Knockdown of DHX9 expression in mDCs blocked the activation of NF-κB and IFN regulatory factor 3 by dsRNA. Collectively, these results suggest that DHX9 is an important RNA sensor that is dependent on IPS-1 to sense pathogenic RNA.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Line
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism*
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Dendritic Cells / virology
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HEK293 Cells
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Humans
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism
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Influenza A virus / immunology
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Interferon Type I / antagonists & inhibitors
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Interferon Type I / biosynthesis
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Mice
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Myeloid Cells / immunology*
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Myeloid Cells / metabolism*
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Myeloid Cells / virology
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nucleic Acid Heteroduplexes / pharmacology
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Poly I-C / metabolism
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Protein Binding / genetics
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Protein Binding / immunology
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RNA, Double-Stranded / genetics
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RNA, Double-Stranded / metabolism*
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RNA, Small Interfering / antagonists & inhibitors
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA, Viral / antagonists & inhibitors
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RNA, Viral / genetics
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RNA, Viral / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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Inflammation Mediators
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Interferon Type I
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MAVS protein, human
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Neoplasm Proteins
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Nucleic Acid Heteroduplexes
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RNA, Double-Stranded
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RNA, Small Interfering
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RNA, Viral
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DHX9 protein, human
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DEAD-box RNA Helicases
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Poly I-C