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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0803663v1 183/9/5526    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Hearn, A. Articles by Rock, K. L. PubMed PubMed Citation Articles by Hearn, A. Articles by Rock, K. L.

The Specificity of Trimming of MHC Class I-Presented Peptides in the Endoplasmic Reticulum¹

Arron Hearn,^* Ian A. York, and Kenneth L. Rock^2*

^*Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; and Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824

Aminopeptidases in the endoplasmic reticulum (ER) can cleave antigenic peptides and in so doing either create or destroy MHC class I-presented epitopes. However, the specificity of this trimming process overall and of the major ER aminopeptidase ERAP1 in particular is not well understood. This issue is important because peptide trimming influences the magnitude and specificity of CD8 T cell responses. By systematically varying the N-terminal flanking sequences of peptides in a cell-free biochemical system and in intact cells, we elucidated the specificity of ERAP1 and of ER trimming overall. ERAP1 can cleave after many amino acids on the N terminus of epitope precursors but does so at markedly different rates. The specificity seen with purified ERAP1 is similar to that observed for trimming and presentation of epitopes in the ER of intact cells. We define N-terminal sequences that are favorable or unfavorable for Ag presentation in ways that are independent from the epitopes core sequence. When databases of known presented peptides were analyzed, the residues that were preferred for the trimming of model peptide precursors were found to be overrepresented in N-terminal flanking sequences of epitopes generally. These data define key determinants in the specificity of Ag processing.

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 grants from the National Institutes of Health (to K.L.R.) and core resources supported by the Diabetes Endocrinology Research Center Grant.

² Address correspondence and reprint requests to Dr. Kenneth L. Rock, Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655. E-mail address: Kenneth.Rock{at}umassmed.edu

³ Abbreviations used in this paper: MHC I, MHC class I; ER, endoplasmic reticulum; ERAP1, endoplasmic reticulum aminopeptidase 1; MFI, mean fluorescence intensity; siRNA, small interfering RNA.

⁴ The online version of this article contains supplemental material.