The Cytosolic Endopeptidase, Thimet Oligopeptidase, Destroys Antigenic Peptides and Limits the Extent of MHC Class I Antigen Presentation

Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Immunity (Impact Factor: 21.56). 04/2003; 18(3):429-40. DOI: 10.1016/S1074-7613(03)00058-X
Source: PubMed


Most antigenic peptides presented on MHC class I molecules are generated by proteasomes during protein breakdown. It is unknown whether these peptides are protected from destruction by cytosolic peptidases. In cytosolic extracts, most antigenic peptides are degraded by the metalloendopeptidase, thimet oligopeptidase (TOP). We therefore examined whether TOP destroys antigenic peptides in vivo. When TOP was overexpressed in cells, class I presentation of antigenic peptides was reduced. In contrast, TOP overexpression didn't reduce presentation of peptides generated in the endoplasmic reticulum or endosomes. Conversely, preventing TOP expression with siRNA enhanced presentation of antigenic peptides. TOP therefore plays an important role in vivo in degrading peptides released by proteasomes and is a significant factor limiting the extent of antigen presentation.

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    • "In agreement with this, degradation of several antigenic peptides, including the well-characterized SIINFEKL, was reduced by the TOP inhibitor Cpp-AAF-pAb in cell lysates [49]. In addition, presentation of epitopes generated from several minigenes and full-length proteins was reduced by overexpression of TOP [50]. Moreover, MHC class I levels at the cellmembrane were reduced after overexpression of TOP, there is more than just recycling beyond the proteasome and was increased upon inhibition of TOP with siRNA [51]. "
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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).
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    • "Therefore, the rapid hydrolysis of these polyglutamine-rich peptides seems likely to be important in preventing or retarding the progression of polyglutamine disorders. Most larger peptides released by proteasomes are initially digested by endopeptidases (8–10), and the resulting shorter peptides are rapidly hydrolyzed to amino acids by various cytosolic aminopeptidases (11–14). "
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    ABSTRACT: A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant α-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule-associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity.
    Human Molecular Genetics 12/2010; 19(23):4573-86. DOI:10.1093/hmg/ddq385 · 6.39 Impact Factor
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    • "The main influence of TPPII on MHC class I processing is likely to be cytosolic destruction of epitopes, since data from two different types of TPPII-deficient mice show increased MHC class I expression [18, 27]. A destructive influence on MHC class I antigen processing has also been reported for Puromycin-sensitive aminopeptidase (PSA) and Thimet Oligopeptidase (TOP) [39, 45]. Sequencing of the MHC class I-bound repertoire in TPPII−/− cells may reveal more about subsets of MHC class I antigens that are negatively or positively influenced by TPPII expression. "
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    ABSTRACT: The tripeptidyl-peptidase II complex consists of repeated 138 kDa subunits, assembled into two twisted strands that form a high molecular weight complex ( > 5 MDa). TPPII, like many other cytosolic peptidases, plays a role in the ubiquitin-proteasome pathway downstream of the proteasome as well as in the production and destruction of MHC class I antigens and degradation of neuropeptides. Tripeptidyl-peptidase II activity is increased in cells with an increased demand for protein degradation, but whether degradation of cytosolic peptides is the only cell biological role for TPPII has remained unclear. Recent data indicated that TPPII translocates into the nucleus to control DNA damage responses in malignant cells, supporting that cytosolic “housekeeping peptidases” may have additional roles in cell biology, besides their contribution to protein turnover. Overall, TPPII has an emerging importance in several cancer-related fields, such as metabolism, cell death control, and control of genome integrity; roles that are not understood in detail. The present paper reviews the cell biology of TPPII and discusses distinct roles for TPPII in the nucleus and cytosol.
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