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An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides

Nature Immunologyvolume 3pages11691176 (2002) | Download Citation



Precursors to major histocompatibility complex (MHC) class I–presented peptides with extra NH2-terminal residues can be efficiently trimmed to mature epitopes in the endoplasmic reticulum (ER). Here, we purified from liver microsomes a lumenal, soluble aminopeptidase that removes NH2-terminal residues from many antigenic precursors. It was identified as a metallopeptidase named “adipocyte-derived leucine” or “puromycin-insensitive leucine-specific” aminopeptidase. However, because we localized it to the ER, we propose it be renamed ER–aminopeptidase 1 (ERAP1). ERAP1 is inhibited by agents that block precursor trimming in ER vesicles and although it trimmed NH2-extended precursors, it spared presented peptides of 8 amino acid and less. Like other proteins involved in antigen presentation, ERAP1 is induced by interferon-γ. When overexpressed in vivo, we found that ERAP1 stimulates the processing and presentation of an antigenic precursor in the ER.

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We thank S. Trombley for assistance in preparing this manuscript, A. Tibebu Kassa in for help with experiments and M. Jedrychowski and S. Gygi for LC-MS/MS analyses. Supported by grants from the NIH (to A. L. G. and K. L. R.).

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Author notes

    • Tomo Saric

    Present address: ATABIS GmbH, Joseph-Stelzmann Str. 50, 50931, Cologne, Germany


  1. Department of Cell Biology, Harvard Medical School, Boston, 02115, MA, USA

    • Tomo Saric
    • , Shih-Chung Chang
    • , Shirley Markant
    •  & Alfred L. Goldberg
  2. Laboratory of Cellular Biochemistry, RIKEN, 2-1 Hirosawa, Wako, 351-0198, Saitama, Japan

    • Akira Hattori
    •  & Masafumi Tsujimoto
  3. Department of Pathology, University of Massachusetts Medical School, Worcester, 06155, MA, USA

    • Ian A. York
    •  & Kenneth L. Rock


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The authors declare no competing financial interests.

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Correspondence to Alfred L. Goldberg.

Supplementary information

  1. Web Fig. 1.

    Gel filtration chromatography of ER-lumenal proteins. (a) The ER-lumenal proteins were fractionated on a Sephacryl S-200 HR size exclusion column. The elution positions of aldolase (158 kD), carbonic anhydrase (29 kD) and cytochrome C (12.4 kD) are marked with arrows. Only one peak of aminopeptidase activity was detected with an apparent molecular weight of ~150 kD (Kav = 0.1083). (b) Fractions encompassing the aminopeptidase peak (23–36) were analyzed by electrophoresis on 4–12% NuPAGE gel and the elution profiles of ERAP1 (A-LAP) and Grp94 (gp96) were determined by immunoblotting. (PDF 508 kb)

  2. Web Fig. 2.

    Recombinant ERAP1 can remove a variety of residues from NH2-extended antigenic peptides. (a) Reactions contained 150 nmol/ml of QLESIINFEKL and 3 μg/ml of recombinant human enzyme. At the indicated times, an aliquot was removed and fractionated by RP-HPLC. (b) Reactions with indicated peptides were performed and analyzed as in a. The amount of a peptide trimmed was calculated by integration of peptide peaks. (PDF 277 kb)

  3. Web Table 1 (PDF 16 kb)

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