title: PIKfyve, a class III lipid kinase, is required for TLR-induced type I IFN production via modulation of ATF3.
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.
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139.
authors.forename: Xinming
authors.initials: X
authors.lastname: Cai
authors.forename: Yongyao
authors.initials: Y
authors.lastname: Xu
authors.forename: You-Me
authors.initials: YM
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Loureiro
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D011743:Pyrimidines; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects / Q000276:immunology; D014227:Triazines / Q000494:pharmacology
chemical_list: D051700:Activating Transcription Factor 3; D006835:Hydrazones; D007093:Imidazoles; D007370:Interferon Type I; D008164:Luminescent Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D011743:Pyrimidines; D051193:Toll-Like Receptors; D014227:Triazines; C492139:PIKFYVE protein, human; C116930:Pikfyve protein, mouse; C504227:apilimod; C402365:resiquimod