A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation.
Intracellular proteins are degraded by the proteasome, and resulting peptides surviving cytoplasmic peptidase activity can be presented by MHC class I molecules. Here, we show that intracellular aminopeptidases degrade peptides within seconds, almost irrespectively of amino acid sequence. N- but not C-terminal extension increases the half-life of peptides until they are 15 amino acids long. Beyond 15 amino acids, peptides are exclusively trimmed by the peptidase TPPII, which displays both exo- and endopeptidase activity. Surprisingly, most proteasomal degradation products are handled by TPPII before presentation by MHC class I molecules. We define three distinct proteolytic activities during antigen processing in vivo. Proteasome-generated peptides relevant for antigen presentation are mostly 15 amino acids or longer. These require TPPII activity for further trimming before becoming substrates for other peptidases and MHC class I. The heterogeneous pool of aminopeptidases will process TPPII products into MHC class I peptides and beyond.
Reits
Eric
E
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Neijssen
Joost
J
Herberts
Carla
C
Benckhuijsen
Willemien
W
Janssen
Lennert
L
Drijfhout
Jan Wouter
JW
Neefjes
Jacques
J
D000595:Amino Acid Sequence; D000626:Aminopeptidases; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015153:Blotting, Western; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000276:immunology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D009097:Multienzyme Complexes / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D012697:Serine Endopeptidases / Q000276:immunology* / Q000378:metabolism*; D013379:Substrate Specificity
D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D010455:Peptides; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex