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J. Biol. Chem., Vol. 282, Issue 52, 37836-37843, December 28, 2007

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Identification of a Lysosomal Peptide Transport System Induced during Dendritic Cell Development^*

Özlem Demirel, Zoe Waibler, Ulrich Kalinke, Frank Grünebach^¶, Silke Appel^¶1, Peter Brossart^¶, Andrej Hasilik^||, Robert Tampé, and Rupert Abele³²

From the Institute of Biochemistry, Biocenter, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, Frankfurt/M. D-60438, the Division of Immunology, Paul-Ehrlich-Institut, Paul-Ehrlich-Strasse 51-59, Langen D-63225, the ^¶Department of Hematology, Oncology and Immunology, Eberhard-Karls-University Tübingen, Otfried-Müller-Strasse 10, Tübingen D-72076, and the ^||Institute of Physiological Chemistry, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, Marburg D-35032, Germany

The delivery of protein fragments to major histocompatibility complex (MHC)-loading compartments of professional antigen-presenting cells is essential in the adaptive immune response against pathogens. Apart from the crucial role of the transporter associated with antigen processing (TAP) for peptide loading of MHC class I molecules in the endoplasmic reticulum, TAP-independent translocation pathways have been proposed but not identified so far. Based on its overlapping substrate specificity with TAP, we herein investigated the ABC transporter ABCB9, also named TAP-like (TAPL). Remarkably, TAPL expression is strongly induced during differentiation of monocytes to dendritic cells and to macrophages. TAPL does not, however, restore MHC class I surface expression in TAP-deficient cells, demonstrating that TAPL alone or in combination with single TAP subunits does not form a functional transport complex required for peptide loading of MHC I in the endoplasmic reticulum. In fact, by using quantitative immunofluorescence and subcellular fractionation, TAPL was detected in the lysosomal compartment co-localizing with the lysosome-associated membrane protein LAMP-2. By in vitro assays, we demonstrate a TAPL-specific translocation of peptides into isolated lysosomes, which strictly requires ATP hydrolysis. These results suggest a mechanism by which antigenic peptides have access to the lysosomal compartment in professional antigen-presenting cells.

Received for publication, March 28, 2007 , and in revised form, October 26, 2007.

^* This work is supported by Studienstiftung des Deutschen Volkes (toÖ_. D.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

³ Present address: Broegelmann Research Lab., The Gade Inst., University of Bergen, N-5021 Bergen, Norway.

¹ To whom correspondence may be addressed: Tel.: 49-69-798-29475; Fax: 49-69-798-29495; E-mail: tampe{at}em.uni-frankfurt.de.

² To whom correspondence may be addressed: Tel.: 49-69-798-29437; Fax: 49-69-798-29495; E-mail: abele{at}em.uni-frankfurt.de.

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