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Allele-Selective Effect of PA28 in MHC Class I Antigen Processing¹

Taketoshi Yamano^2,*, Hidetoshi Sugahara^2,*, Shusaku Mizukami^*, Shigeo Murata, Tomoki Chiba, Keiji Tanaka, Katsuyuki Yui^¶ and Heiichiro Udono^3,*

^* Laboratory for Immunochaperones, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Tsurumi, Yokohama, Japan; Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan; Graduate School of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba City, Ibaraki, Japan; Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Honkomagome, Bunkyo-ku, Tokyo, Japan; and ^¶ Division of Immunology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto, Nagasaki, Japan

PA28 is an IFN--inducible proteasome activator and its genetic ablation causes complete loss of processing of certain Ags, but not all of them. The reason why this occurs and how PA28 influences the formation of peptide repertoires for MHC class I molecules remains unknown. In this study, we show the allele-specific role of PA28 in Ag processing. Retrovirus-transduced overexpression of PA28 decreased expression of K^d (D^d) while it increased K^b and L^d on the cell surface. By contrast, overexpression of PA28C5, a mutant carrying a deletion of its five C-terminal residues and capable of attenuating the activity of endogenous PA28, produced the opposite effect on expression of those MHC class I molecules. Moreover, knockdown of both PA28 and β by small-interfering RNA profoundly augmented expression of K^d and D^d, but not of L^d, on the cell surface. Finally, we found that PA28-associated proteasome preferentially digested within epitopic sequences of K^d, although correct C-terminal flankings were removed, which in turn hampered production of K^d ligands. Our results indicate that whereas PA28 negatively influences processing of K^d (D^d) ligands, thereby, down-regulating Ag presentation by those MHC class I molecules, it also efficiently produces K^b (L^d) epitopes, leading to up-regulation of the MHC molecules.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, Japan.

² T.Y. and H.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Heiichiro Udono, Laboratory for Immunochaperones, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Tsurumi, Yokohama 230-0045, Japan. E-mail address: udonoh{at}rcai.riken.jp

⁴ Abbreviations used in this paper: siRNA, small-interfering RNA; LC, liquid chromatography; MS, mass spectrometry; VSV, vesicular stomatitis virus; M, macrophage; MCMV, murine CMV; CSP, circumsporozoite protein; NP, nucleoprotein.