Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing.

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.
Mesh Terms:
Antigen Presentation, CD8-Positive T-Lymphocytes, Cytomegalovirus Infections, Endoplasmic Reticulum, Glycoproteins, HeLa Cells, Histocompatibility Antigens Class I, Humans, Immediate-Early Proteins, Membrane Proteins, Mutation, Oxidation-Reduction, Peptides, Proteasome Endopeptidase Complex, Protein Disulfide-Isomerases, Protein Structure, Tertiary, RNA, Small Interfering, Sulfhydryl Compounds, Transfection
Cell
Date: Oct. 20, 2006
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