[HTML][HTML] 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 …
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 …
Summary
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.
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