Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3' UTR

Elliot Goodenough, Tara M. Robinson, Matthew B. Zook, Kevin M. Flanigan, John F. Atkins, Michael T. Howard, Laurence C. Eisenlohr

Research output: Contribution to journalArticlepeer-review

Abstract

Aminoglycosides have been proposed as therapies for genetic disorders caused by nonsense mutations, because of their capacity to enhance translational read-through of premature termination codons (PTCs), thereby permitting expression of functional fulllength protein. However, a potential consequence of this strategy is the development of an autoimmune response to HLA-presented epitopes encoded downstream of the PTC or other stop codons. Using a recombinant virus-expression system in tissue culture and in mice, we demonstrate that gentamicin can induce expression and MHC class I presentation of a model epitope encoded downstream of a PTC at levels sufficient to activate CD8+ T cells. The degree of read-through-derived peptide presentation varies with the sequence of the stop codon and +1 nucleotide. Additionally, we applied a mass spectrometry exploration of the HLA class I peptide repertoire of gentamicin-treated cells and identified multiple peptides derived from read-through of conventional stop codons. These results substantiate the possibility of self-reactivity to cryptic epitopes revealed by stop codon read-through therapies and potentially other therapeutic approaches involving compounds that alter translational fidelity.

Original languageEnglish (US)
Pages (from-to)5670-5675
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number15
DOIs
StatePublished - Apr 15 2014

Keywords

  • Antigen presentation
  • Autoimmunity
  • Recoding

ASJC Scopus subject areas

  • General

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