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J. Biol. Chem., Vol. 282, Issue 17, 12749-12754, April 27, 2007

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The N-terminal Flanking Region of the TRP2_360–368 Melanoma Antigen Determines Proteasome Activator PA28 Requirement for Epitope Liberation^*

Kathrin Textoris-Taube, Peter Henklein, Sylvie Pollmann, Theresa Bergann, Hardy Weisshoff, Ulrike Seifert, Ilse Drung, Clemens Mügge, Alice Sijts^¶, Peter-Michael Kloetzel¹, and Ulrike Kuckelkorn

From the Institut für Biochemie, Charité-Universitätsmedizin, D-10117 Berlin, Germany, Institut für Chemie, Humboldt-Universität, D-12489 Berlin, Germany, and ^¶Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, 3584 CL Utrecht, Netherlands

Proteasomes are known to produce major histocompatibility complex (MHC) class I ligands from endogenous antigens. The interferon--inducible proteasome activator PA28 plays an important role in the generation of MHC ligands by proteasomes. Generation of the HLA-A^*0201 restricted melanoma antigen TRP2_360–368 by the proteasome has been shown to be dependent on the function of PA28 in vitro and in vivo (Sun, Y., Sijts, A. J., Song, M., Janek, K., Nussbaum, A. K., Kral, S., Schirle, M., Stevanovic, S., Paschen, A., Schild, H., Kloetzel, P. M., and Schadendorf, D. (2002) Cancer Res. 62, 2875–2882). Here we analyzed the role of the epitope sequence environment in determining this PA28 dependence. Experiments using the melanoma TRP2_288–296 epitope and the murine cytomegalovirus-derived pp89 epitope precursor peptide for epitope replacement revealed that the TRP2_360–368 flanking sequences can transfer PA28 dependence onto otherwise PA28 independent epitopes. Moreover, the N-terminal flanking sequence is sufficient to establish PA28 dependence of an epitope by allowing PA28-induced coordinated dual cleavages. These results show that N-terminal flanking sequences strongly influence epitope generation efficiency and that PA28 function is particularly relevant for the generation of normally poorly excised peptide products.

Received for publication, December 19, 2006 , and in revised form, February 8, 2007.

^* This work was supported by Grants Sonderforschungsbereich (SFB) 421 (to P.-M. K.), SFB/TR 19 (to U. K.), and Deutsche Forschungsgemeinschaft Ku1261 (to U. K.). 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 To whom correspondence should be addressed: Monbijoustrasse 2, D-10117 Berlin, Germany. Tel.: 49-30-450-528071; Fax: 49-30-450-528921; E-mail: p-m.kloetzel{at}charite.de.

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