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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigen Presentation*
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CD8-Positive T-Lymphocytes / metabolism
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Cytomegalovirus Infections / metabolism
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Endoplasmic Reticulum / enzymology
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Glycoproteins / genetics
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Glycoproteins / immunology
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Glycoproteins / metabolism*
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HeLa Cells
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Histocompatibility Antigens Class I / immunology
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Histocompatibility Antigens Class I / metabolism*
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / immunology
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Immediate-Early Proteins / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mutation
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Oxidation-Reduction
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Peptides / immunology
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Peptides / metabolism*
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Proteasome Endopeptidase Complex / metabolism
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Protein Disulfide-Isomerases / genetics
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Protein Disulfide-Isomerases / metabolism*
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Protein Structure, Tertiary / genetics
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RNA, Small Interfering / genetics
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Sulfhydryl Compounds / metabolism
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Transfection
Substances
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Glycoproteins
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Histocompatibility Antigens Class I
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Immediate-Early Proteins
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Membrane Proteins
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Peptides
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RNA, Small Interfering
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Sulfhydryl Compounds
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US3 protein, cytomegalovirus
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Proteasome Endopeptidase Complex
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Protein Disulfide-Isomerases