Phosphatidylinositol‐3‐kinase and Akt are required for RIG‐I‐mediated anti‐viral signalling through cross‐talk with IPS‐1

Summary Retinoic acid‐inducible gene I (RIG‐I) is a cytosolic pattern‐recognition receptor that recognizes viruses and triggers anti‐viral immune responses. Activation of intracellular RIG‐I signalling is mediated through interferon‐β (IFN‐β) promoter stimulator‐1 (IPS‐1), an adaptor of RIG‐I, which...

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Bibliographic Details
Published in:Immunology 2015-02, Vol.144 (2), p.312-320
Main Authors: Yeon, Sang Hyeon, Song, Moon Jung, Kang, Hye‐Ri, Lee, Joo Young
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - immunology
Animals
Antiviral Agents - pharmacology
Cells, Cultured
Chromones - pharmacology
DEAD Box Protein 58
DEAD-box RNA Helicases - immunology
Dimerization
Enzyme Activation - immunology
Enzyme Inhibitors - pharmacology
HEK293 Cells
Humans
Immune system
innate immunity
Interferon Inducers - pharmacology
Interferon Regulatory Factor-3 - biosynthesis
Interferon Regulatory Factor-3 - immunology
Interferon Regulatory Factor-3 - metabolism
Interferon-beta - biosynthesis
macrophages
Macrophages - immunology
Medical research
Mice
Mice, Inbred C57BL
Morpholines - pharmacology
Original
pattern‐recognition receptor
Phosphatidylinositol 3-Kinase - antagonists & inhibitors
Phosphatidylinositol 3-Kinase - immunology
Phosphorylation
Poly I-C - pharmacology
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - immunology
Respirovirus Infections - immunology
RNA Interference
RNA, Small Interfering
Sendai virus - immunology
Signal Transduction - immunology
type I interferon
Viral infections
virus infection
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Summary:Summary Retinoic acid‐inducible gene I (RIG‐I) is a cytosolic pattern‐recognition receptor that recognizes viruses and triggers anti‐viral immune responses. Activation of intracellular RIG‐I signalling is mediated through interferon‐β (IFN‐β) promoter stimulator‐1 (IPS‐1), an adaptor of RIG‐I, which induces IFN regulatory factor (IRF) 3 activation and type I IFN expression. The phosphatidylinositol‐3‐kinase (PI3K) and Akt pathway is activated in host immune cells upon viral infection. However, the mechanism as to how they work in RIG‐I signalling has not been fully elucidated. Therefore, we investigated the role of PI3K and Akt in the regulation of RIG‐I‐mediated IRF3 activation and type I IFN expression in macrophages. Our results show that Sendai virus infection, which is recognized by RIG‐I, led to IRF3 activation and IFN‐β expression and these responses were attenuated by the PI3K inhibitor (LY294002) and an Akt dominant‐negative mutant in the macrophage cell line(RAW264.7). IRF3 phosphorylation and dimerization as well as IFN‐β expression induced by a synthetic RIG‐I agonist, short poly(I:C), were suppressed by LY294002 or siRNA‐Akt in bone marrow‐derived macrophages. Suppression of PI3K and Akt using a dominant‐negative mutant and siRNA knockdown resulted in attenuation of IRF3 activation and IFN‐β expression induced by RIG‐I itself or its adaptor, IPS‐1. Association of Akt with IPS‐1 increased with short poly(I:C) stimulation and required the pleckstrin homology domain of Akt and caspase‐recruitment domain in IPS‐1. Collectively, our results show that PI3K and Akt are required downstream of IPS‐1 for RIG‐I‐mediated anti‐viral immune responses. The results describe a novel, interactive relationship between RIG‐I downstream signalling molecules resulting in efficient anti‐viral immunity.
ISSN:0019-2805
1365-2567
DOI:10.1111/imm.12373