1. Processing of Tumor Antigens
Tumor antigens recognized by Cytolytic T Lymphocytes (CTL) consist of peptides that are presented by MHC molecules at the cell surface and derive from intracellular proteins that are degraded by the proteasome. The intracellular pathway leading from the protein to the peptide/MHC complex is known as "antigen processing". Our group focuses on the proteasome and recently described a new mode of production of antigenic peptides by the proteasome, based on cutting and pasting peptide fragments to form a new spliced peptide. The first example was a peptide derived from human melanocyte protein gp100. This antigenic peptide is nine-amino acid long and is produced by the splicing of two fragments that were initially non-contiguous in the parental protein. The splicing is made by the proteasome, is tightly coupled to the proteolytic reaction, and appears to occur by transpeptidation involving an acyl-enzyme intermediate. We also described a second example of spliced peptide, where the two fragments are rearranged before splicing. We are currently working on additional candidates.
We are also studying the processing differences between the standard proteasome, which is present in most cells, and the immunoproteasome which is found in dendritic cells and in cells exposed to interferon-gamma. Several tumor antigens were found to be processed differently by the two proteasome types, usually because of a preferential cleavage made by one or the other proteasome within the antigenic peptide itself. We also study the splicing capacity of the two proteasome types.
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