The Journal of Experimental Medicine
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Published online 8 July 2002 doi:10.1084/jem.20011922
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© Rockefeller University Press, 0022-1007/2002/7/185/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 2, July 15, 2002 185-196
Two Distinct Pathways Mediated by PA28 and hsp90 in Major Histocompatibility Complex Class I Antigen Processing

Taketoshi Yamano1, Shigeo Murata2, Naoki Shimbara3, Noriaki Tanaka4, Tomoki Chiba2, Keiji Tanaka2, Katsuyuki Yui1 and Heiichiro Udono1

1 Department of Molecular Medicine, Division of Immunology, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan
2 Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Science and Technology Corporation, Tokyo 113-8613, Japan
3 UpScience, Incorporated, Yokohama 244-8588, Japan
4 First Department of Surgery, Okayama University Medical School, Okayama 700, Japan

Address correspondence to Heiichiro Udono, Department of Molecular Medicine, Division of Immunology, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan. Phone: 81-95-849-7071; Fax: 81-95-849-7073; E-mail: udonoh{at}net.nagasaki-u.ac.jp

Major histocompatibility complex (MHC) class I ligands are mainly produced by the proteasome. Herein, we show that the processing of antigens is regulated by two distinct pathways, one requiring PA28 and the other hsp90. Both hsp90 and PA28 enhanced the antigen processing of ovalbumin (OVA). Geldanamycin, an inhibitor of hsp90, almost completely suppressed OVA antigen presentation in PA28{alpha}-/-/ß-/- lipopolysaccharide blasts, but not in wild-type cells, indicating that hsp90 compensates for the loss of PA28 and is essential in the PA28-independent pathway. In contrast, treatment of cells with interferon (IFN)-{gamma}, which induces PA28 expression, abrogated the requirement of hsp90, suggesting that IFN-{gamma} enhances the PA28-dependent pathway, whereas it diminishes hsp90-dependent pathway. Importantly, IFN-{gamma} did not induce MHC class I expressions in PA28-deficient cells, indicating a prominent role for PA28 in IFN-{gamma}–stimulated peptide supply. Thus, these two pathways operate either redundantly or specifically, depending on antigen species and cell type.

Key Words: antigen presentation • cytotoxic T lymphocytes • immunity active • macrophage activation • transplantation immunology


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