title: Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation.
abstract: The MHC class I antigen presentation pathway allows the immune system to distinguish between self and nonself. Despite extensive research on the processing of antigenic peptides, little is known about their origin. Here, we show that mRNAs carrying premature stop codons that prevent the production of full-length proteins via the nonsense-mediated decay pathway still produce a majority of peptide substrates for the MHC class I pathway by a noncanonical mRNA translation process. Blocking the interaction of the translation initiation factor eIF4E with the cap structure suppresses the synthesis of full-length proteins but has only a limited effect on the production of antigenic peptides. These results reveal an essential cell biological function for a class of translation products derived during the pioneer round of mRNA translation and will have important implications for understanding how the immune system detects cells harboring pathogens and generates tolerance.
authors.affiliation: Cibles Therapeutiques, Institut National de la Santé et de la Recherche Médicale U940, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010 Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Apcher
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Daskalogianni
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lejeune
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Manoury
authors.forename: Gabriela
authors.initials: G
authors.lastname: Imhoos
authors.forename: Lea
authors.initials: L
authors.lastname: Heslop
authors.forename: Robin
authors.initials: R
authors.lastname: Fåhraeus
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001483:Base Sequence; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005805:Genes, MHC Class I; D057809:HEK293 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D051379:Mice; D018448:Models, Immunological; D010442:Peptide Chain Initiation, Translational; D010455:Peptides / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis; D012315:RNA Caps / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D012315:RNA Caps; D012333:RNA, Messenger