title: Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing.
abstract: Activated CD8(+) T cells discriminate infected and tumor cells from normal self by recognizing MHC class I-bound peptides on the surface of antigen-presenting cells. The mechanism by which MHC class I molecules select optimal peptides against a background of prevailing suboptimal peptides and in a considerably proteolytic ER environment remained unknown. Here, we identify protein disulfide isomerase (PDI), an enzyme critical to the formation of correct disulfide bonds in proteins, as a component of the peptide-loading complex. We show that PDI stabilizes a peptide-receptive site by regulating the oxidation state of the disulfide bond in the MHC peptide-binding groove, a function that is essential for selecting optimal peptides. Furthermore, we demonstrate that human cytomegalovirus US3 protein inhibits CD8(+) T cell recognition by mediating PDI degradation, verifying the functional relevance of PDI-catalyzed peptide editing in controlling intracellular pathogens. These results establish a link between thiol-based redox regulation and antigen processing.
authors.affiliation: Department of Biological Sciences, National Creative Research Center for Antigen Presentation, Seoul National University, Seoul 151-747, South Korea.
authors.forename: Boyoun
authors.initials: B
authors.lastname: Park
authors.forename: Sungwook
authors.initials: S
authors.lastname: Lee
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Kim
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Cho
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.forename: Sunglim
authors.initials: S
authors.lastname: Cho
authors.forename: Kwangseog
authors.initials: K
authors.lastname: Ahn
mesh_terms: D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014162:Transfection
chemical_list: D006023:Glycoproteins; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; C095111:US3 protein, cytomegalovirus; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases