Abstract
During infection with an RNA virus, the DExD/H-box RNA helicases RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5) activate the interferon regulatory factor 3 (IRF3), nuclear factor κB (NF-κB), c-Jun amino-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways through an unknown mechanism involving the adaptor protein MAVS (mitochondrial antiviral signaling). We used a Drosophila misexpression screen to identify DEAH-box polypeptide 15 (DHX15) as an activator of the p38 MAPK pathway. Human DHX15 contributed to the activation of the NF-κB, JNK, and p38 MAPK pathways, but not the IRF3 pathway, in response to the synthetic double-stranded RNA analog poly(I:C) (polyinosinic-polycytidylic acid), and DHX15 was required for optimal cytokine production in response to poly(I:C) and infection with RNA virus. DHX15 physically interacted with MAVS and mediated the MAVS-dependent activation of the NF-κB and MAPK pathways. Furthermore, DHX15 was required for poly(I:C)- and RNA virus-dependent, MAVS-mediated apoptosis. Thus, our findings indicate that, in RIG-I-like receptor signaling, DHX15 specifically stimulates the NF-κB and MAPK pathways downstream of MAVS and contributes to MAVS-mediated cytokine production and apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
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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Apoptosis / genetics
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Blotting, Western
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Cell Line
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / cytology
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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Encephalomyocarditis virus / physiology
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HEK293 Cells
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HeLa Cells
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Host-Pathogen Interactions
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Humans
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Interferon-beta / genetics
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Interferon-beta / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Signaling System*
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Mutation
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NF-kappa B / metabolism*
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Poly I-C / genetics
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RNA Helicases / genetics
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RNA Helicases / metabolism*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Sendai virus / physiology
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Drosophila Proteins
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Interleukin-6
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MAVS protein, human
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Tumor Necrosis Factor-alpha
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Interferon-beta
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JNK Mitogen-Activated Protein Kinases
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DHX15 protein, human
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RNA Helicases
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Poly I-C