Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard proteasome results in differential antigen presentation.
The immunoproteasome (IP) is usually viewed as favoring the production of antigenic peptides presented by MHC class I molecules, mainly because of its higher cleavage activity after hydrophobic residues, referred to as the chymotrypsin-like activity. However, some peptides have been found to be better produced by the standard proteasome. The mechanism of this differential processing has not been described. By studying the processing of three tumor antigenic peptides of clinical interest, we demonstrate that their differential processing mainly results from differences in the efficiency of internal cleavages by the two proteasome types. Peptide gp100(209-217) (ITDQVPSFV) and peptide tyrosinase369-377 (YMDGTMSQV) are destroyed by the IP, which cleaves after an internal hydrophobic residue. Conversely, peptide MAGE-C2(336-344) (ALKDVEERV) is destroyed by the standard proteasome by internal cleavage after an acidic residue, in line with its higher postacidic activity. These results indicate that the IP may destroy some antigenic peptides due to its higher chymotrypsin-like activity, rather than favor their production. They also suggest that the sets of peptides produced by the two proteasome types differ more than expected. Considering that mature dendritic cells mainly contain IPs, our results have implications for the design of immunotherapy strategies.
Chapiro
Jacques
J
Ludwig Institute for Cancer Research, Brussels Branch, and Cellular Genetics Unit, Université Catholique de Louvain (UCL), Brussels, Belgium.
Claverol
Stéphane
S
Piette
Fanny
F
Ma
Wenbin
W
Stroobant
Vincent
V
Guillaume
Benoît
B
Gairin
Jean-Edouard
JE
Morel
Sandra
S
Burlet-Schiltz
Odile
O
Monsarrat
Bernard
B
Boon
Thierry
T
Van den Eynde
Benoît J
BJ
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D000951:Antigens, Neoplasm; D001665:Binding Sites; D002460:Cell Line; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology* / Q000378:metabolism*; D058951:gp100 Melanoma Antigen
D000941:Antigens; D000951:Antigens, Neoplasm; C405429:MAGEC2 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009842:Oligopeptides; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase; D046988:Proteasome Endopeptidase Complex