HSP70 and HSP90 differentially regulate translocation of extracellular antigen to the cytosol for cross-presentation

Yu Kato, Chiaki Kajiwara, Ikuo Ishige, Shusaku Mizukami, Chihiro Yamazaki, Shingo Eikawa, Kazuhiro Kakimi, Heiichiro Udono

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number745962
JournalAutoimmune Diseases
Volume1
Issue number1
DOIs
Publication statusPublished - 2012

Fingerprint

Cross-Priming
Cytosol
Antigens
Endosomes
Cytotoxic T-Lymphocytes
Proteasome Endopeptidase Complex
Type 1 Diabetes Mellitus
Dendritic Cells
Autoimmune Diseases
Neoplasms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology and Microbiology (miscellaneous)
  • Immunology

Cite this

HSP70 and HSP90 differentially regulate translocation of extracellular antigen to the cytosol for cross-presentation. / Kato, Yu; Kajiwara, Chiaki; Ishige, Ikuo; Mizukami, Shusaku; Yamazaki, Chihiro; Eikawa, Shingo; Kakimi, Kazuhiro; Udono, Heiichiro.

In: Autoimmune Diseases, Vol. 1, No. 1, 745962, 2012.

Research output: Contribution to journalArticle

Kato, Yu ; Kajiwara, Chiaki ; Ishige, Ikuo ; Mizukami, Shusaku ; Yamazaki, Chihiro ; Eikawa, Shingo ; Kakimi, Kazuhiro ; Udono, Heiichiro. / HSP70 and HSP90 differentially regulate translocation of extracellular antigen to the cytosol for cross-presentation. In: Autoimmune Diseases. 2012 ; Vol. 1, No. 1.
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