Tripeptidyl Peptidase II Is the Major Peptidase Needed to Trim Long Antigenic Precursors, but Is Not Required for Most MHC Class I Antigen Presentation

Department of Molecular and Cell Biology, Harvard University, Cambridge, Massachusetts, United States
The Journal of Immunology (Impact Factor: 4.92). 09/2006; 177(3):1434-43. DOI: 10.4049/jimmunol.177.3.1434
Source: PubMed


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.

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Available from: Alfred L Goldberg, Jul 24, 2015
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    • "Some of the intracellular enzymes can process both proteins and peptides. For example, tripeptidyl-peptidase II primarily cleaves three amino acid residues from the N-terminal of peptides/proteins, and also functions as an endopeptidase [35] [39] [40]. Several other cytosolic endopeptidases are known for their selectivity for oligopeptides and inability to directly cleave proteins into peptides. "
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    ABSTRACT: Peptidomics techniques have identified hundreds of peptides that are derived from proteins present mainly in the cytosol, mitochondria, and/or nucleus; these are termed intracellular peptides to distinguish them from secretory pathway peptides that function primarily outside of the cell. The proteasome and thimet oligopeptidase participate in the production and metabolism of intracellular peptides. Many of the intracellular peptides are common among mouse tissues and human cell lines analyzed and likely to perform a variety of functions within cells. Demonstrated functions include the modulation of signal transduction, mitochondrial stress, and development; additional functions will likely be found for intracellular peptides.
    Full-text · Article · Jun 2014 · EuPA Open Proteomics
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    • "Altogether, the generation of most MHC class I-bound peptides appears to be independent of TPPII [27]. Nevertheless, the processing of peptides longer than 15 residues requires TPPII [23] [24], but only a small fraction of the peptides released by the proteasome falls into that size range [24] [30] [31]. "
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    ABSTRACT: Tripeptidyl peptidase II is the largest known eukaryotic peptidase. It has been described as a multi-purpose peptidase, which, in addition to its house-keeping function in intracellular protein degradation, plays a role in several vital cellular processes such as antigen processing, apoptosis, or cell division, and is involved in diseases like muscle wasting, obesity, and in cancer. Biochemical studies and bioinformatics have identified TPPII as a subtilase, but its structure is very unusual: it forms a large homooligomeric complex (6 MDa) with a spindle-like shape. Recently, the high-resolution structure of TPPII homodimers (300 kDa) was solved and a hybrid structure of the holocomplex built of 20 dimers was obtained by docking it into the EM-density. Here, we summarize our current knowledge about TPPII with a focus on structural aspects. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
    Full-text · Article · Jul 2011 · Biochimica et Biophysica Acta
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    • "One of the most intriguing peptidases is TPPII, which displays both exopeptidase activity as it can cleave tripeptides from a free N-terminus (hence its name) and endopeptidase activity [58]. It has been suggested that TPPII is essential for the processing of all peptides above the length of fifteen amino acids [33] [59], and compensates for the maximum peptide size that can be degraded by most other exopeptidases. Since the proteasome generates fragments ranging from three to twenty-four amino acids [34], TPPII may even generate alternative C-termini of epitopes by its endopeptidase activity to generate specific subsets of antigenic peptides [60]. "
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    ABSTRACT: Het proteasoom zorgt voor afbraak van eiwitten. Dat gebeurt in stappen – eerst genereert het proteasoom kleine peptiden die peptidases vervolgens verder afbreken tot individuele aminozuren. Een deel wordt gepresenteerd aan het immuunsysteem. Een subgroep daarvan is niet - zoals werd aangenomen - gemaakt door tripeptidyl peptidase II (TPPII) maar door metallopeptidases. Deze bevinding kan implicaties hebben voor het detecteren van kankercellen en cellen die door virussen geïnfecteerd zijn. Raspe onderzocht ook de functie van peptidases bij neurodegeneratieve ziekten als Alzheimer en Huntington die gepaard gaan met ophoping van moeilijk afbreekbare eiwitfragmenten. Bij Huntington bemoeilijkt een lange herhaling van hetzelfde aminozuur de afbraak van die eiwitfragmenten. Raspe vond twee peptidases (PSA en TPPII) die dergelijke ophopingen verminderen. PSA doet dat niet op de gebruikelijke wijze maar door het activeren van een ander opruimmechanisme, autofagie (waarbij de cel zichzelf als het ware opeet).
    Preview · Article · Jan 2011
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