Thimet Oligopeptidase (EC 3.4.24.15), a Novel Protein on the Route of MHC Class I Antigen Presentation

Silva, Célio Lopes; Portaro, Fernanda Calheta Vieira; Bonato, Vânia Luiza Deperon; Camargo, Antônio Carlos Martins de; Ferro, Emer S.

doi:10.1006/bbrc.1999.0250

Cited by 79 publications

(74 citation statements)

References 24 publications

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“…Purified TOP, A CTL epitope from M. Tuberculosis Hsp65 with undefined aa sequence has previously been shown to rely on TOP 36 . A possible role for TOP in the protection of some cytosolic peptides from further destruction has been documented 37 , however, this could not be confirmed 38 .…”

Section: Discussionmentioning

confidence: 99%

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

et al. 2010

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Cytoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C-terminus of these CTL epitopes is predominantly generated by the proteasome.Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus, and a clinically important epitope from melanoma-protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing and nardilysin contributed to both C-terminal and N-terminal CTL epitope generation. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

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Section: Discussionmentioning

confidence: 99%

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

et al. 2010

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“…These include at least two enzymes, PSA and BH, that have been reported to be inhibited by AAF-cmk (32,36). In addition, TO and the IFN-␥-inducible LA have been proposed to act as either productive or destructive postproteasomal trimming enzymes (33)(34)(35)49). To test whether any of these proteases contributes to productive NP 147-155 generation, recombinant vacs expressing each of the four proteases were constructed.…”

Section: Overexpression Of Other Proteasesmentioning

confidence: 99%

“…In addition to TPP II, several reports have demonstrated that other nonproteasomal cytosolic proteases may contribute to the generation or destruction of antigenic peptides via post proteasomal trimming. These include LA (33), thymet oligopeptidase (TO) (34,35), bleomycin hydrolase (BH), and puromycin-sensitive aminopeptidase (PSA) (32,36). In addition to these cytosolic proteases, ER-resident amino peptidase (ERAAP or ERAP1 in the mouse, ERAP1/2 complex in the human) can further trim peptides at the N terminus once they have been transported via TAP (10 -13).…”

mentioning

confidence: 99%

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Wherry

Golovina

Morrison

et al. 2006

The Journal of Immunology

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The proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP147–155 of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently “proteasome-independent” epitopes remain poorly defined. We have examined the generation of NP147–155 and a second proteasome-dependent NP epitope, NP50–57, using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP147–155, 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP50–57 or NP147–155, and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP147–155 epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.

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“…In contrast, several cytosolic peptidases potentially involved in this process have been identified. Those include puromycin-sensitive aminopeptidase, bleomycin hydrolase, thimet oligopeptidase, and leucyl aminopeptidase (13)(14)(15). A common feature of these peptidases is that they display a broad specificity and do not lead to an enrichment of the exact antigenic peptide.…”

mentioning

confidence: 99%

The Final N-Terminal Trimming of a Subaminoterminal Proline-Containing HLA Class I-Restricted Antigenic Peptide in the Cytosol Is Mediated by Two Peptidases

Lévy

Burri

Morel

et al. 2002

The Journal of Immunology

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The proteasome produces MHC class I-restricted antigenic peptides carrying N-terminal extensions, which are trimmed by other peptidases in the cytosol or within the endoplasmic reticulum. In this study, we show that the N-terminal editing of an antigenic peptide with a predicted low TAP affinity can occur in the cytosol. Using proteomics, we identified two cytosolic peptidases, tripeptidyl peptidase II and puromycin-sensitive aminopeptidase, that trimmed the N-terminal extensions of the precursors produced by the proteasome, and led to a transient enrichment of the final antigenic peptide. These peptidases acted either sequentially or redundantly, depending on the extension remaining at the N terminus of the peptides released from the proteasome. Inhibition of these peptidases abolished the CTL-mediated recognition of Ag-expressing cells. Although we observed some proteolytic activity in fractions enriched in endoplasmic reticulum, it could not compensate for the loss of tripeptidyl peptidase II/puromycin-sensitive aminopeptidase activities.

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Thimet Oligopeptidase (EC 3.4.24.15), a Novel Protein on the Route of MHC Class I Antigen Presentation

Cited by 79 publications

References 24 publications

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

The Final N-Terminal Trimming of a Subaminoterminal Proline-Containing HLA Class I-Restricted Antigenic Peptide in the Cytosol Is Mediated by Two Peptidases

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