title: The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation.
abstract: Most antigenic peptides presented on MHC class I molecules are generated by proteasomes during protein breakdown. It is unknown whether these peptides are protected from destruction by cytosolic peptidases. In cytosolic extracts, most antigenic peptides are degraded by the metalloendopeptidase, thimet oligopeptidase (TOP). We therefore examined whether TOP destroys antigenic peptides in vivo. When TOP was overexpressed in cells, class I presentation of antigenic peptides was reduced. In contrast, TOP overexpression didn't reduce presentation of peptides generated in the endoplasmic reticulum or endosomes. Conversely, preventing TOP expression with siRNA enhanced presentation of antigenic peptides. TOP therefore plays an important role in vivo in degrading peptides released by proteasomes and is a significant factor limiting the extent of antigen presentation.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: York
authors.forename: Annie X Y
authors.initials: AX
authors.lastname: Mo
authors.forename: Kristen
authors.initials: K
authors.lastname: Lemerise
authors.forename: Wanyong
authors.initials: W
authors.lastname: Zeng
authors.forename: Yuelei
authors.initials: Y
authors.lastname: Shen
authors.forename: Carmela R
authors.initials: CR
authors.lastname: Abraham
authors.forename: Tomo
authors.initials: T
authors.lastname: Saric
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D000941:Antigens / Q000378:metabolism*; D019556:COS Cells; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D010455:Peptides / Q000276:immunology* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex
chemical_list: D000941:Antigens; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D010455:Peptides; D003546:Cysteine Endopeptidases; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; D046988:Proteasome Endopeptidase Complex