Tripeptidyl peptidase II is the major peptidase needed to trim long antigenic precursors, but is not required for most MHC class I antigen presentation.
Recent reports concluded that tripeptidyl peptidase (TPPII) is essential for MHC class I Ag presentation and that the proteasome in vivo mainly releases peptides 16 residues or longer that require processing by TPPII. However, we find that eliminating TPPII from human cells using small interfering RNA did not decrease the overall supply of peptides to MHC class I molecules and reduced only modestly the presentation of SIINFEKL from OVA, while treatment with proteasome inhibitors reduced these processes dramatically. Purified TPPII digests peptides from 6 to 30 residues long at similar rates, but eliminating TPPII in cells reduced the processing of long antigenic precursors (14-17 residues) more than short ones (9-12 residues). Therefore, TPPII appears to be the major peptidase capable of processing proteasome products longer than 14 residues. However, proteasomes in vivo (like purified proteasomes) release relatively few such peptides, and these peptides processed by TPPII require further trimming in the endoplasmic reticulum (ER) by ER aminopeptidase 1 for presentation. Taken together, these observations demonstrate that TPPII plays a specialized role in Ag processing and one that is not essential for the generation of most presented peptides. Moreover, these findings reveal that three sequential proteolytic steps (by proteasomes, TPPII, and then ER aminopepsidase 1) are required for the generation of a subset of epitopes.
York
Ian A
IA
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Ian.York@umassmed.edu
Bhutani
Nidhi
N
Zendzian
Sophia
S
Goldberg
Alfred L
AL
Rock
Kenneth L
KL
D000595:Amino Acid Sequence; D000626:Aminopeptidases; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004527:Egg Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011817:Rabbits; D012697:Serine Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D004527:Egg Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; C110366:OVA-8; D010446:Peptide Fragments; D011498:Protein Precursors; D034741:RNA, Small Interfering; D015842:Serine Proteinase Inhibitors; D010047:Ovalbumin; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D046988:Proteasome Endopeptidase Complex