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The Murine Cytomegalovirus pp89 Immunodominant H-2L^d Epitope Is Generated and Translocated into the Endoplasmic Reticulum as an 11-Mer Precursor Peptide¹

Christine Knuehl^*, Pieter Spee, Thomas Ruppert^2,*, Ulrike Kuckelkorn^*, Peter Henklein^*, Jacques Neefjes and Peter-M. Kloetzel^3,*

^* Institute of Biochemistry, Medical Faculty, Charité, Humboldt University, Berlin, Germany; and Division of Tumor Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands

The 20S proteasome is involved in the processing of MHC class I-presented Ags. A number of epitopes is known to be generated as precursor peptides requiring trimming either before or after translocation into the endoplasmic reticulum (ER). In this study, we have followed the proteasomal processing and TAP-dependent ER translocation of the immunodominant epitope of the murine CMV immediate early protein pp89. For the first time, we experimentally linked peptide generation by the proteasome system and TAP-dependent ER translocation. Our experiments show that the proteasome generates both an N-terminally extended 11-mer precursor peptide as well as the correct H2-L^d 9-mer epitope, a process that is accelerated in the presence of PA28. Our direct peptide translocation assays, however, demonstrate that only the 11-mer precursor peptide is transported into the ER by TAPs, whereas the epitope itself is not translocated. In consequence, our combined proteasome/TAP assays show that the 11-mer precursor is the immunorelevant peptide product that requires N-terminal trimming in the ER for MHC class I binding.

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