title: Using intein catalysis to probe the origin of major histocompatibility complex class I-presented peptides.
abstract: All vertebrate nucleated cells generate peptides from their expressed gene products and then display them at the cell surface bound to MHC class I molecules. This allows CD8(+) T cells to detect and eliminate abnormal cells that are synthesizing foreign proteins, e.g., from viruses or mutations. To permit the immune system to more uniformly monitor a cell's proteins, regardless of their half-life or location, it has been thought that the products of rapid degradation of the mistakes of protein synthesis (defective ribosomal products, DRiPs) preferentially contribute to the class I-presented peptides. However, using intein catalysis to generate peptide sequences exclusively by posttranslational splicing of mature proteins, we show here that presented peptides can be generated from fully folded and functional proteins. Remarkably, the presentation of peptides from two model mature proteins is just as efficient as from newly synthesized proteins subject to errors in translation or folding. These results indicate that for the constructs we have analyzed, DRiPs are not a more efficient source of class I peptides for antigen presentation than the turnover of mature functional proteins. Accordingly, our data suggest that one of the major ways the immune system evaluates the health of cells is by monitoring the breakdown products of the proteome.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Diego J
authors.initials: DJ
authors.lastname: Farfán-Arribas
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002384:Catalysis; D002460:Cell Line; D003001:Cloning, Molecular; D005455:Fluorescent Antibody Technique; D005805:Genes, MHC Class I / Q000235:genetics*; D007157:Immunologic Surveillance / Q000235:genetics / Q000276:immunology*; D047668:Inteins; D051379:Mice; D008822:Mice, Transgenic; D010452:Peptide Biosynthesis; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D020543:Proteome / Q000235:genetics* / Q000276:immunology
chemical_list: D010455:Peptides; D020543:Proteome