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Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1662-7. doi: 10.1073/pnas.0711365105. Epub 2008 Jan 23.

Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation.

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1
Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.

Abstract

CD8(+) T cells recognize peptide fragments of endogenously synthesized antigens of cancers or viruses, presented by MHC I molecules. Such antigen presentation requires the generation of peptides in the cytosol, their passage to the endoplasmic reticulum, loading of MHC I with peptides, and transport of MHC I-peptide complexes to the cell surface. Heat-shock protein (hsp) 90 is a cytosolic chaperone known to associate with peptide and peptide precursors of MHC I epitopes. We report here that treatment of cells with hsp90 inhibitors leads to generation of "empty" MHC I caused by inhibited loading of MHC I with peptides. Inhibition of hsp90 does not inhibit synthesis of MHC I, nor does it affect the activity of proteasomes. Hsp90-inhibited cells, such as proteasome-inhibited cells, are poor stimulators of T lymphocytes. The role of hsp90 in presentation of an ovalbumin epitope is shown to be at a postproteasomal step: hsp90 associates with N-terminally extended precursors of the SIINFEHL epitope, and such peptides are depleted from hsp90 preparations in hsp90-inhibited cells. Inhibition of hsp90 in the antigen donor cell compromises their ability to cross-prime. Conversely, stressed cells expressing elevated hsp90 levels show a heat-shock factor-dependent, enhanced ability to cross-prime. These results demonstrate a substantial role for hsp90 in chaperoning of antigenic peptides in direct and indirect presentation. The introduction of a stress-inducible component in these pathways has significant implications for their modulation during fever and infection.

PMID:
18216248
PMCID:
PMC2234201
DOI:
10.1073/pnas.0711365105
[Indexed for MEDLINE]
Free PMC Article
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