An antigenic peptide produced by reverse splicing and double asparagine deamidation

Alexandre Dalet, Paul F. Robbins, Vincent Stroobant, Nathalie Vigneron, Yong F. Li, Mona El-Gamil, Ken Ichi Hanada, James C. Yang, Steven A. Rosenberg, Benoit̂ J. Van Den Eyndea

Research output: Contribution to journalArticlepeer-review

Abstract

A variety of unconventional translational and posttranslational mechanisms contribute to the production of antigenic peptides, thereby increasing the diversity of the peptide repertoire presented by MHC class I molecules. Here, we describe a class I-restricted peptide that combines several posttranslational modifications. It is derived from tyrosinase and recognized by tumor-infiltrating lymphocytes isolated from a melanoma patient. This unusual antigenic peptide is made of two noncontiguous tyrosinase fragments that are spliced together in the reverse order. In addition, it contains two aspartate residues that replace the asparagines encoded in the tyrosinase sequence. We confirmed that this peptide is naturally presented at the surface of melanoma cells, and we showed that its processing sequentially requires translation of tyrosinase into the endoplasmic reticulum and its retrotranslocation into the cytosol, where deglycosylation of the two asparagines by peptide-N-glycanase turns them into aspartates by deamidation. This process is followed by cleavage and splicing of the appropriate fragments by the standard proteasome and additional transport of the resulting peptide into the endoplasmic reticulum through the transporter associated with antigen processing (TAP).

Original languageEnglish (US)
Pages (from-to)E323-E331
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number29
DOIs
StatePublished - Jul 19 2011
Externally publishedYes

Keywords

  • Antigen processing
  • Peptide splicing
  • Tumor antigen

ASJC Scopus subject areas

  • General

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