Unanticipated antigens: translation initiation at CUG with leucine.
Major histocompatibility class I molecules display tens of thousands of peptides on the cell surface for immune surveillance by T cells. The peptide repertoire represents virtually all cellular translation products, and can thus reveal a foreign presence inside the cell. These peptides are derived from not only conventional but also cryptic translational reading frames, including some without conventional AUG codons. To define the mechanism that generates these cryptic peptides, we used T cells as probes to analyze the peptides generated in transfected cells. We found that when CUG acts as an alternate initiation codon, it can be decoded as leucine rather than the expected methionine residue. The leucine start does not depend on an internal ribosome entry site-like mRNA structure, and its efficiency is enhanced by the Kozak nucleotide context. Furthermore, ribosomes scan 5' to 3' specifically for the CUG initiation codon in a eukaryotic translation initiation factor 2-independent manner. Because eukaryotic translation initiation factor 2 is frequently targeted to inhibit protein synthesis, this novel translation mechanism allows stressed cells to display antigenic peptides. This initiation mechanism could also be used at non-AUG initiation codons often found in viral transcripts as well as in a growing list of cellular genes.
Schwab
Susan R
SR
Division of Immunology, Department of Molecular and Cell Biology, University of California, Berkeley, California, USA.
Shugart
Jessica A
JA
Horng
Tiffany
T
Malarkannan
Subramaniam
S
Shastri
Nilabh
N
D020121:5' Untranslated Regions; D000818:Animals; D000941:Antigens / Q000737:chemistry*; D019556:COS Cells; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D003062:Codon; D018387:Codon, Initiator; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007930:Leucine / Q000737:chemistry*; D008715:Methionine / Q000737:chemistry; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry; D010442:Peptide Chain Initiation, Translational; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D016364:Reading Frames; D012270:Ribosomes / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014162:Transfection
D020121:5' Untranslated Regions; D000941:Antigens; D003062:Codon; D018387:Codon, Initiator; D015852:Eukaryotic Initiation Factor-2; D009711:Nucleotides; D010455:Peptides; D012333:RNA, Messenger; D008715:Methionine; D007930:Leucine