Two new proteases in the MHC class I processing pathway

Stoltze, Lars; Schirle, Markus; Schwarz, Gerold; Schröter, Christian; Thompson, Michael; Hersh, Louis B.; Kalbacher, Hubert; Stevanović, Stefan; Rammensee, Hans‐Georg; Schild, Hansjörg

doi:10.1038/80852

Cited by 234 publications

(197 citation statements)

References 32 publications

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“…Often peptides are produced by the proteasome with an extension on their amino-termini (Cascio et al 2001). Aminopeptidases in the cytosol or in the endoplasmic reticulum trim the Nterminal of these peptides (Stoltze et al 2000b). Therefore, a possible MHC ligand can be defined as fragments generated by two consecutive predicted cleavages, which are eight to 15 residues apart.…”

Section: The Immunoproteasome Generates More Mhc Ligandsmentioning

confidence: 99%

“…This co-evolution is limited to the specificity of C-terminal of MHC ligands and the specificity of the P1 position in the immunoproteasome digests. The P1 0 and P2 0 positions do not become the N-terminal of MHC ligands, due to additional trimming that takes place in the cytoplasm and the endoplasmic reticulum (Cascio et al 2001;Stoltze et al 2000b). Therefore, the specificity of the immunoproteasome and the constitutive proteasome has not diverged at these positions (Fig.…”

Section: The Immunoproteasome Generates More Mhc Ligandsmentioning

confidence: 99%

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Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon , the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.

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Section: The Immunoproteasome Generates More Mhc Ligandsmentioning

confidence: 99%

Section: The Immunoproteasome Generates More Mhc Ligandsmentioning

confidence: 99%

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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“…This transport is facilitated by binding of the peptides to TAP. Once inside the ER, further N-terminal trimming of the peptides may occur [5,8], as well as binding of some of the peptides to MHC class I. After binding, the MHC class I:peptide complex is transported to the surface of the cell, where it may be recognized by CTL.…”

Section: Introductionmentioning

confidence: 99%

An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

Larsen

Lundegaard

Lamberth³

et al. 2005

Eur. J. Immunol.

285

254

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Reverse immunogenetic approaches attempt to optimize the selection of candidate epitopes, and thus minimize the experimental effort needed to identify new epitopes. When predicting cytotoxic T cell epitopes, the main focus has been on the highly specific MHC class I binding event. Methods have also been developed for predicting the antigen-processing steps preceding MHC class I binding, including proteasomal cleavage and transporter associated with antigen processing (TAP) transport efficiency. Here, we use a dataset obtained from the SYFPEITHI database to show that a method integrating predictions of MHC class I binding affinity, TAP transport efficiency, and Cterminal proteasomal cleavage outperforms any of the individual methods. Using an independent evaluation dataset of HIV epitopes from the Los Alamos database, the validity of the integrated method is confirmed. The performance of the integrated method is found to be significantly higher than that of the two publicly available prediction methods BIMAS and SYFPEITHI. To identify 85% of the epitopes in the HIV dataset, 9% and 10% of all possible nonamers in the HIV proteins must be tested when using the BIMAS and SYFPEITHI methods, respectively, for the selection of candidate epitopes. This number is reduced to 7% when using the integrated method. In practical terms, this means that the experimental effort needed to identify an epitope in a hypothetical protein with 85% probability is reduced by 20-30% when using the integrated method. The method is available at

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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%

“…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. In some instances, the generation of the accurate N terminus of antigenic peptides can be mediated by more than one peptidase in a redundant manner (13).…”

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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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Two new proteases in the MHC class I processing pathway

Cited by 234 publications

References 32 publications

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

An integrative approach to CTL epitope prediction: A combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions

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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