HSP70 and HSP90 Differentially Regulate Translocation of Extracellular Antigen to the Cytosol for Cross-Presentation

被引:17
|
作者
Kato, Yu [1 ]
Kajiwara, Chiaki [1 ]
Ishige, Ikuo [2 ]
Mizukami, Shusaku [3 ]
Yamazaki, Chihiro [3 ]
Eikawa, Shingo [3 ]
Kakimi, Kazuhiro [4 ]
Udono, Heiichiro [1 ,3 ]
机构
[1] RCAI, RIKEN Yokohama Inst, Lab Immunochaperones, Yokohama, Kanagawa 2300045, Japan
[2] BM Equipment CO Itd, Tokyo 1130034, Japan
[3] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Immunol, Okayama 7008558, Japan
[4] Tokyo Univ Hosp, Dept Immunotherapeut, Bunkyo Ku, Tokyo 1138655, Japan
关键词
D O I
10.1155/2012/745962
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Antigens (Ag) from cancer or virus-infected cells must be internalized by dendritic cells (DCs) to be presented to CD8(+) T cells, which eventually differentiate into Ag-specific cytotoxic T lymphocytes (CTLs) that destroy cancer cells and infected cells. This pathway is termed cross-presentation and is also implicated as an essential step in triggering autoimmune diseases such as Type I diabetes. Internalized Ag locates within endosomes, followed by translocation through a putative pore structure spanning endosomal membranes into the cytosol, where it is degraded by the proteasome to generate antigen peptides. During translocation, Ag is believed to be unfolded since the pore size is too narrow to accept native Ag structure. Here, we show that paraformaldehyde-fixed, structurally inflexible Ag is less efficient in cross-presentation because of diminished translocation into the cytosol, supporting the "unfolded Ag" theory. We also show that HSP70 inhibitors block both endogenous and cross-presentation. ImageStream analysis revealed that the inhibition in cross-presentation is not due to blocking of Ag translocation because a HSP70 inhibitor rather facilitates the translocation, which is in marked contrast to the effect of an HSP90 inhibitor that blocks Ag translocation. Our results indicate that Ag translocation to the cytosol in cross-presentation is differentially regulated by HSP70 and HSP90.
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页数:11
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