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EMBO reports 8, 10, 945–951 (2007)
doi:10.1038/sj.embor.7401065
AOP Published online: 14 September 2007
A novel cytosolic class I antigen-processing pathway for endoplasmic-reticulum-targeted proteins
Eva Schlosser1*, Carolina Otero1*, Christine Wuensch1, Benedikt Kessler2, Mariola Edelmann2, René Brunisholz3, Ingo Drexler4, Daniel F Legler5, 6 & Marcus Groettrup1, 5, 6
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1 Division of Immunology, Department of Biology, Postbox M661, Universitatstrasse 10, University of Constance, Konstanz D-78457, Germany
2 The Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, Oxford University, Oxford OX3 7BN, UK
3 Protein Analysis Group, Functional Genomics Center Zürich, Zürich CH-8057, Switzerland
4 GSF National Research Center for Environment and Health, Institute for Molecular Virology, Munich, Germany
5 Biotechnology Institute Thurgau (BITg), University of Konstanz, Kreuzlingen CH-8280, Switzerland
6 These authors share senior authorship
To whom correspondence should be addressed
Marcus Groettrup Tel: +49 7531 882130; Fax: +49 7531 883102; E-mail: marcus.groettrup@uni-konstanz.de
* These authors contributed equally to this work
Received 1 March 2007; Accepted 3 August 2007; Published online 14 September 2007.
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Abstract
Proteins bearing an endoplasmic reticulum (ER) leader are inserted into the ER followed by cleavage of the signal peptide. Major histocompatibility complex class I-restricted T-cell epitopes can be generated from these proteins by the proteasome after retrotranslocation into the cytosol. Here, we show that an HLA-A*0201-restricted epitope from prostate stem cell antigen contains the cleavage site of the ER signal peptidase. The resulting cleavage products fail to bind to HLA-A*0201 and are not recognized by T lymphocytes. As processing of prostate stem cell antigen by signal peptidase occurs immediately after co-translational insertion, the epitope must be processed from polypeptides that have never reached the ER. The processing of this epitope depends on the proteasome and the transporter associated with antigen processing and shows a novel pathway of class I processing that relies on the failure of ER-targeted proteins to reach their target compartment.
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