A Major Role for TPP II 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 TPP II, which displays both exo-and endopeptidase activity. Surprisingly, most proteasomal degradation products are handled by TPP II 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 TPP II activity for further trimming before becoming substrates for other peptidases and MHC class I. The heterogeneous pool of aminopeptidases will process TPP II products into MHC class I peptides and beyond.