Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type I IFN induction via targeting to static early endosome.
Recent studies have suggested that TLR9 signaling in early endosomes leads to IFN-alpha production by plasmacytoid dendritic cells (pDCs), whereas TLR9 signaling in late endosomes induces pDC maturation, IL-6, and TNF-alpha secretion. In this study, we show that human DNA as well as CpG-oligodeoxynucleotides (ODNs) in complex with heat shock protein 90 (Hsp90) stimulate pDCs to produce large quantities of IFN-alpha. The Hsp90-CpG-A complexes are targeted into the Rab5+, early endosomal Ag 1+-static early endosome postinternalization by DCs, suggesting that preferential sorting of Hsp90-chaperoned self-DNA/CpG-ODNs to the static endosome is required for signaling through TLR9 for IFN-alpha production. Interestingly, Hsp90-mediated preferential static early endosomal translocation of CpG-ODNs triggers robust IFN-alpha production from murine conventional DCs. Thus, extracellular Hsp90 converts inert self-DNA/CpG-ODNs into a potent trigger of IFN-alpha production via spatiotemporal regulation.
Okuya
Koichi
K
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Tamura
Yasuaki
Y
Saito
Keita
K
Kutomi
Goro
G
Torigoe
Toshihiko
T
Hirata
Koichi
K
Sato
Noriyuki
N
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002469:Cell Separation; D004247:DNA / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D021381:Protein Transport; D051217:Toll-Like Receptor 9 / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; C408982:CPG-oligonucleotide; D018841:HSP90 Heat-Shock Proteins; D007370:Interferon Type I; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA