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Toll-like receptor 9 trafficking and signaling for type I interferons requires PIKfyve activity.
- Source :
-
International immunology [Int Immunol] 2015 Sep; Vol. 27 (9), pp. 435-45. Date of Electronic Publication: 2015 Apr 29. - Publication Year :
- 2015
-
Abstract
- Toll-like receptors (TLRs) traffic to distinct membranes for signaling. TLR7 and TLR9 recognize viral nucleic acids in the endosomes and induce robust anti-viral program. Signaling from these TLRs bifurcate at the level of distinct endosomal compartments, namely VAMP3(+) and LAMP(+) endosomes, to mediate the induction of cytokine and type I interferon (IFN) genes, respectively. The formation of the TLR9 endosome competent for IFNs induction requires AP-3. Phosphoinositides (PIs) mark distinct subcellular membranes and control membrane trafficking. However, their role in TLR trafficking and signaling in different dendritic cell (DC) subsets remains unclear. Here, we examined the role of phosphatidylinositol 3P 5-kinase, PIKfyve, in TLR9 trafficking and signaling. We demonstrate that inhibition of PIKfyve activity preferentially blocks TLR9 signaling for type I IFN induction in FLT3L-bone marrow-derived DCs. By confocal microscopy using RAW264.7 cells, we show that trafficking of both TLR9 and CpG to the LAMP1(+) compartment was blocked by PIKfyve inhibitor treatment, whereas their trafficking to the VAMP3(+) endosome remained intact. Further, AP-3 recruitment to TLR9 endosomes was impaired by PIKfyve inhibition. These data indicate that PIKfyve provides critical PIs necessary for the formation of endosome from which TLR9 signals to induce type I IFNs.<br /> (© The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Animals
Cell Line
Cell Membrane metabolism
DNA-Binding Proteins metabolism
Dendritic Cells metabolism
Endosomes metabolism
Lysosomal Membrane Proteins metabolism
Mice
Mice, Inbred C57BL
Protein Transport physiology
Toll-Like Receptor 7 metabolism
Transcription Factors metabolism
Vesicle-Associated Membrane Protein 3 metabolism
Interferon Type I metabolism
Phosphatidylinositol 3-Kinases metabolism
Signal Transduction physiology
Toll-Like Receptor 9 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2377
- Volume :
- 27
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International immunology
- Publication Type :
- Academic Journal
- Accession number :
- 25925170
- Full Text :
- https://doi.org/10.1093/intimm/dxv021