title: Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway.
abstract: TAP can efficiently transport peptides up to twice as long as those bound to MHC class I molecules, suggesting a role for endoplasmic reticulum (ER) proteases in the trimming of TAP-transported peptides. To better define ER processing of antigenic peptides, we examined the capacity of TAP-deficient cells to present determinants derived from ER-targeted proteins encoded by recombinant vaccinia viruses. TAP-deficient cells failed to present antigenic peptides from internal locations in secreted proteins to MHC class I-restricted T lymphocytes. The same peptides were liberated from the C termini of a secreted protein and the lumenal domains of two membrane proteins delivered to the ER via different routes. These findings suggest that proteases in the secretory compartment can liberate C-terminal antigenic peptides from virtually any context. We propose that this activity often participates in the removal of N-terminal extensions from TAP-transported peptides, thereby creating optimally sized products for MHC class I binding. We further demonstrate that ER trimming of C termini can occur if we express an appropriate carboxypeptidase in the secretory pathway. The absence of such trimming under normal circumstances suggests that carboxypeptidase activity is generally deficient in the ER, consistent with the concordance between the specificity of TAP and MHC class I molecules for the same types of C-terminal residues.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-0440, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Snyder
authors.forename: I
authors.initials: I
authors.lastname: Bacík
authors.forename: J W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: T W
authors.initials: TW
authors.lastname: Behrens
authors.forename: J R
authors.initials: JR
authors.lastname: Bennink
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001692:Biological Transport / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology*; D010450:Endopeptidases / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D010455:Peptides; D010450:Endopeptidases