Leucine-tRNA Initiates at CUG Start Codons for Protein Synthesis and Presentation by MHC Class I

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Science  29 Jun 2012:
Vol. 336, Issue 6089, pp. 1719-1723
DOI: 10.1126/science.1220270

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Noncanonical Pathway

The textbook view of translation of messenger RNA to protein is that it is always initiated from open reading frames (ORFs) that begin with an AUG codon (encodes methionine) by an initiator methionine-bound transfer RNA (tRNA). There is evidence, however, that some polypeptides are produced from non–AUG-initiated ORFs. Starck et al. (p. 1719; see the Perspective by Dever) used a variety of biochemical techniques to determine the underlying mechanism for such nontraditional translation initiation. Comparison of translation initiation from AUG-initiated ORFs with those beginning with leucine CUG-initiated ORFs revealed that cells can use an elongator Leu-tRNA to initiate translation at CUG codons. CUG-initiated peptides were presented by major histocompatibility class I molecules and could activate T cells.


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-tRNAiMet) 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.

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