Abstract
Type I IFN plays a key role in antiviral responses. It also has been shown that deregulation of type I IFN expression following abnormal activation of TLRs contributes to the pathogenesis of systemic lupus erythematosus. In this study, we find that PIKfyve, a class III lipid kinase, is required for endolysosomal TLR-induced expression of type I IFN in mouse and human cells. PIKfyve binds to phosphatidylinositol 3-phosphate and synthesizes phosphatidylinositol 3,5-bisphosphate, and plays a critical role in endolysosomal trafficking. However, PIKfyve modulates type I IFN production via mechanisms independent of receptor and ligand trafficking in endolysosomes. Instead, pharmacological or genetic inactivation of PIKfyve rapidly induces expression of the transcription repressor ATF3, which is necessary and sufficient for suppression of type I IFN expression by binding to its promoter and blocking its transcription. Thus, we have uncovered a novel phosphoinositide-mediated regulatory mechanism that controls TLR-mediated induction of type I IFN, which may provide a new therapeutic indication for the PIKfyve inhibitor.
MeSH terms
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Activating Transcription Factor 3 / genetics
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Activating Transcription Factor 3 / immunology*
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Activating Transcription Factor 3 / metabolism
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Animals
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Cell Line
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Cell Line, Tumor
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HEK293 Cells
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Humans
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Hydrazones
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Imidazoles / pharmacology
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Immunoblotting
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Interferon Type I / genetics
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Interferon Type I / immunology*
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Interferon Type I / metabolism
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Microscopy, Confocal
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Morpholines / pharmacology
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Oligonucleotide Array Sequence Analysis
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology*
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Protein Binding / immunology
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Pyrimidines
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Toll-Like Receptors / genetics
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Toll-Like Receptors / immunology*
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Toll-Like Receptors / metabolism
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Transcriptome / drug effects
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Transcriptome / immunology
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Triazines / pharmacology
Substances
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Activating Transcription Factor 3
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Hydrazones
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Imidazoles
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Interferon Type I
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Luminescent Proteins
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Morpholines
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Pyrimidines
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Toll-Like Receptors
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Triazines
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PIKFYVE protein, human
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Pikfyve protein, mouse
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apilimod
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resiquimod