Cutting Edge: H-2Ld Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing

Infantes, Susana; Samino, Yolanda; Lorente, Elena; Jiménez, Mercedes; García, Ruth; Val, Margarita Del; López, Daniel

doi:10.4049/jimmunol.0901560

Cited by 20 publications

(18 citation statements)

References 30 publications

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“…This model, by definition, shifts the burden of substrate selection to the MHC and away from ERAP1. At the same time it has been proposed the MHC class I binding can protect peptides from ERAP1 hydrolysis (50,53). Although no similar experiments have been performed for ERAP2, all known ERAP1 and ERAP2 structures, including the ones presented here, are not consistent with an "onto-MHC" peptide trimming model both due to the limited access to the catalytic site as well as the necessary topology of binding so that scissile bond catalysis can take place (31).…”

Section: Discussionmentioning

confidence: 49%

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Mpakali

Giastas

Mathioudakis

et al. 2015

Journal of Biological Chemistry

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Background: ER aminopeptidases generate antigenic peptides, but how they recognize their substrates is unclear. Results: We solved crystal structures of ERAP2 in complex with a substrate analogue and a peptide product. Conclusion: The peptides were found trapped inside a large cavity adjacent to the catalytic site. Significance: Interactions of the substrate with the internal cavity can result in both substrate permissiveness and limited sequence bias.

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Section: Discussionmentioning

confidence: 49%

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Mpakali

Giastas

Mathioudakis

et al. 2015

Journal of Biological Chemistry

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“…One μl of sample was mixed with 0,8 μl of saturated α-cyanohydroxycinnamic acid matrix in the same solution. One microliter of the mixture was dried and subjected to analysis as previously described [12]. …”

Section: Methodsmentioning

confidence: 99%

Concerted In Vitro Trimming of Viral HLA-B27-Restricted Ligands by Human ERAP1 and ERAP2 Aminopeptidases

et al. 2013

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In the classical human leukocyte antigen (HLA) class I antigen processing and presentation pathway, the antigenic peptides are generated from viral proteins by multiple proteolytic cleavages of the proteasome (and in some cases other cytosolic proteases) and transported to the endoplasmic reticulum (ER) lumen where they are exposed to aminopeptidase activity. In human cells, two different ER-resident enzymes, ERAP1 and ERAP2, can trim the N-terminally extended residues of peptide precursors. In this study, the possible cooperative effect of generating five naturally processed HLA-B27 ligands by both proteases was analyzed. We identified differences in the products obtained with increased detection of natural HLA-B27 ligands by comparing double versus single enzyme digestions by mass spectrometry analysis. These in vitro data suggest that each enzyme can use the degradation products of the other as a substrate for new N-terminal trimming, indicating concerted aminoproteolytic activity of ERAP 1 and ERAP2.

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“…Recently, published data indicate that an N-terminal-elongated 15-mer precursor peptide derived from HIV is protected against degradation when bound to class I molecules, whereas it can be trimmed by ERAP1 if added in the absence of MHC class I molecules [42]. For MART-1 processing, possibly due to its low MHC-binding affinity, it seems likely that free precursor and epitope peptides are degraded by ERAP before they can sufficiently bind to MHC class I molecules, which results in strongly reduced MART-1 epitope presentation on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, epitopes with high MHC-binding affinity would settle into the peptide-binding groove of the MHC class I molecule once they are trimmed to the correct size where they are protected against further destruction [41]. In contrast, peptides with low MHC class I binding affinity will be released again from the peptide-binding groove and will be further trimmed and destroyed.Recently, published data indicate that an N-terminal-elongated 15-mer precursor peptide derived from HIV is protected against degradation when bound to class I molecules, whereas it can be trimmed by ERAP1 if added in the absence of MHC class I molecules [42]. For MART-1 processing, possibly due to its low MHC-binding affinity, it seems likely that free precursor and epitope peptides are degraded by ERAP before they can sufficiently bind to MHC class I molecules, which results in strongly reduced MART-1 epitope presentation on the cell surface.…”

mentioning

confidence: 99%

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

et al. 2015

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Eur. J. Immunol. 2015. 45: 3257-3268 IntroductionThe differentiation antigen melanoma antigen recognized by T cells/melanoma antigen A (thereafter named MART-1) has been a major target in antigen-specific immunotherapy of malignant melanoma and in particular its immunodominant HLA-A*0201-restricted CD8 + T-cell epitope MART-1 26(27)-35 [1,2]. But clinical efficacy of different MART-1-specific therapies has only been limited. In vitro studies employing high-affinity MART-1-specific CD8 + T-cell clones demonstrated that some melanoma cell lines, despite expression of MART-1 and the corresponding HLA allele, were only barely recognized by specific T cells [3]. While different variants of the MART-1 epitope (including the MART-1 [26][27][28][29][30][31][32][33][34][35] 10-mer and the MART-1 27-35 9-mer) have been identified, only the 9-mer epitope can be eluted in significant amounts from the cell surface of melanoma cells [4]. This suggests that mechanisms related to antigen processing interfere with efficient generation of the 10-mer MART-1 26-35 epitope in tumor cells. It has been demonstrated that MART-1 26-35 epitope processing is controlled by the proteasome, the major proteolytic machinery of the cytosol [5]. The standard proteasome (SP) contains the catalytic subunits β1, β2, and β5, whereas exposure of cells to IFN-γ enhances expression and incorporation of the immunosubunits β1i/LMP2 (LMP, low molecular weight protein), β2i/MECL-1 (multicatalytic endopeptidase complex-like 1), and β5i/LMP7 into nascent proteasome complexes. Immunosubunit-containing proteasomes represent catalytic properties that are different from that of SPs [6]. Interestingly, IFN-γ has been described to interfere with efficient MART-1 26-35 epitope generation due to the activity of the proteasome immunosubunits β1i/LMP2 and β5i/LMP7 [5,7,8].To degrade cellular proteins in an ubiquitin-dependent manner, 20S catalytic core particles are connected to 19S regulatory complexes. In the presence of IFN-γ, the expression of PA28α/β (PA, proteasome activator), an activator complex that in combination with the 19S regulatory complex and the 20S proteasome forms so-called PA28-20S-19S hybrid proteasome complexes, is induced [9,10]. The PA28 has been associated with positive effects on epitope processing due to facilitating the access of substrates to the active sites of the proteasome. Generation of the TRP2 360-368 epitope derived from the melanoma antigen tyrosinase-related protein 2 (TRP2) was shown to be completely dependent on PA28 activity by influencing the proteasomal structure and cleavage specificity [11]. Moreover, IFN-γ induces the expression of the ER-resident aminopeptidases ERAP1/2 that trim epitope precursor peptides released into the ER to bind MHC class I molecules [12][13][14][15]. In this context, increased epitope generation has been preferentially attributed to ERAP1, whereas the role of ERAP2 in epitope processing is still under debate [16]. Varying expression levels of ERAP1/2 have been described in different tumor enti...

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Cutting Edge: H-2Ld Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing

Abstract: Material

Cited by 20 publications

References 30 publications

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Concerted In Vitro Trimming of Viral HLA-B27-Restricted Ligands by Human ERAP1 and ERAP2 Aminopeptidases

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition

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Cutting Edge: H-2Ld Class I Molecule Protects an HIV N-Extended Epitope from In Vitro Trimming by Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing

Abstract: Material

Cited by 20 publications

References 30 publications

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Concerted In Vitro Trimming of Viral HLA-B27-Restricted Ligands by Human ERAP1 and ERAP2 Aminopeptidases

The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐126‐35‐specific T‐cell recognition

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The proteasome immunosubunits, PA28 and ER‐aminopeptidase 1 protect melanoma cells from efficient MART‐1_26‐35‐specific T‐cell recognition