Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells.
Bottom Line: In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs.Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway.Our data indicate that targeting of the antigen to a "static" early endosome by Hsp90 is essential for efficient cross-presentation.
Affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.Show MeSH
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Mentions: We then examined whether Hsp90–precursor peptide complex was cross-presented by human Mo-DCs through an endosomal pathway after targeting to the static early endosome. We used chloroquine for inhibition of endosomal acidification and primaquine for inhibition of the membrane recycling pathway. As shown in Figure6(a), Mo-DCs that were pre-incubated with increasing concentrations of chloroquine completely blocked cross-presentation of Hsp90–survivin-2B75-93 precursor peptide complex but had no substantial effect on survivin-2B80-88 peptide presentation. These results indicated that cross-presentation of Hsp90–precursor peptide complex depended on endosomal acidification, possibly including proteolysis by endosomal proteases. Moreover, Mo-DC incubated with primaquine could not present the Hsp90-chaperoned precursor peptide-derived survivin-2B80-88 peptide to CTL (Fig.6b). These results indicated that the Hsp90-chaperoned precursor peptide or processed peptide entered recycling endosomes and were transferred onto recycling MHC class I molecules.
Affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.