Leucine-tRNA initiates at CUG start codons for protein synthesis and presentation by MHC class I

Science. 2012 Jun 29;336(6089):1719-23. doi: 10.1126/science.1220270.


Effective immune surveillance by cytotoxic T cells requires newly synthesized polypeptides for presentation by major histocompatibility complex (MHC) class I molecules. These polypeptides are produced not only from conventional AUG-initiated, but also from cryptic non-AUG-initiated, reading frames by distinct translational mechanisms. Biochemical analysis of ribosomal initiation complexes at CUG versus AUG initiation codons revealed that cells use an elongator leucine-bound transfer RNA (Leu-tRNA) to initiate translation at cryptic CUG start codons. CUG/Leu-tRNA initiation was independent of the canonical initiator tRNA (AUG/Met-tRNA(i)(Met)) pathway but required expression of eukaryotic initiation factor 2A. Thus, a tRNA-based translation initiation mechanism allows non-AUG-initiated protein synthesis and supplies peptides for presentation by MHC class I molecules.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics*
  • Antigen-Presenting Cells / immunology
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Initiator*
  • HeLa Cells
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Hybridomas / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Chain Initiation, Translational
  • Protein Biosynthesis / genetics*
  • RNA, Transfer, Leu*
  • T-Lymphocytes / immunology


  • Codon, Initiator
  • Histocompatibility Antigens Class I
  • RNA, Transfer, Leu