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Most antigenic peptides presented by MHC class I molecules result from the degradation of intracellular proteins by the proteasome. In lymphoid tissues and cells exposed to IFNγ, the standard proteasome is replaced by the immunoproteasome, in which all of the standard catalytic subunits β1, β2, and β5 are replaced by their inducible counterparts β1i, β2i, and β5i, which have different cleavage specificities. The immunoproteasome thereby shapes the repertoire of antigenic peptides. The existence of additional forms of proteasomes bearing a mixed assortment of standard and inducible catalytic subunits has been suggested. Using a new set of unique subunit-specific antibodies, we have now isolated, quantified, and characterized human proteasomes that are intermediate between the standard proteasome and the immunoproteasome. They contain only one (β5i) or two (β1i and β5i) of the three inducible catalytic subunits of the immunoproteasome. These intermediate proteasomes represent between one-third and one-half of the proteasome content of human liver, colon, small intestine, and kidney. They are also present in human tumor cells and dendritic cells. We identified two tumor antigens of clinical interest that are processed exclusively either by intermediate proteasomes β5i (MAGE-A3(271-279)) or by intermediate proteasomes β1i-β5i (MAGE-A10(254-262)). The existence of these intermediate proteasomes broadens the repertoire of antigens presented to CD8 T cells and implies that the antigens presented by a given cell depend on their proteasome content.

Original publication

DOI

10.1073/pnas.1009778107

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

26/10/2010

Volume

107

Pages

18599 - 18604

Keywords

Amino Acid Sequence, Animals, Antigen Presentation, Antigens, Neoplasm, Cell Line, Tumor, Histocompatibility Antigens Class I, Humans, Mice, Mice, Knockout, Molecular Sequence Data, Neoplasm Proteins, Proteasome Endopeptidase Complex, Protein Subunits, Recombinant Proteins, Sequence Homology, Amino Acid