Deletion of Immunoproteasome Subunits Imprints on the Transcriptome and Has a Broad Impact on Peptides Presented by Major Histocompatibility Complex I molecules

Verteuil, Danielle de; Muratore-Schroeder, Tara L.; Granados, Diana Paola; Fortier, Marie-Hélène; Hardy, Marie-Pierre; Bramoullé, Alexandre; Caron, Étienne; Vincent, Krystel; Mader, Sylvie; Lemieux, Sébastien; Thibault, Pierre; Perreault, Claude

doi:10.1074/mcp.m900566-mcp200

Cited by 77 publications

(106 citation statements)

References 61 publications

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“…to isolate newly generated MHC class I peptides. A significant proportion of peptides is, however, nonspecific for the MHC class I molecule (38,39). In fact, by comparing the number of MAE-extracted peptides from wild-type and ␤2-microglobulin knockout cells -the latter expressing virtually no detectable level of cell surface MHC class I molecules -about 40 -60% of the identified peptides were determined to be contaminants, i.e.…”

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confidence: 99%

“…Analysis of MHC class I and II peptide ligands from cells isolated in mouse primary tissue were reported with limited success given the high number of mice needed to perform an experiment (37)(38)(39)(40). In terms of translational potential, primary human tissues are highly attractive (Fig.…”

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confidence: 99%

“…Until recently, MAE was used to isolate MHC class I peptides from various cell lines, bone-marrow-derived dendritic cells, and primary thymocytes (5,38,39,48,50). The MAE approach is cell-surface-specific and can be repeated over time from the same cell population, e.g.…”

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confidence: 99%

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Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

Caron

Kowalewski

Koh

et al. 2015

Molecular & Cellular Proteomics

198

118

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The myriad of peptides presented at the cell surface by class I and class II major histocompatibility complex (MHC) molecules are referred to as the immunopeptidome and are of great importance for basic and translational science. For basic science, the immunopeptidome is a critical component for understanding the immune system; for translational science, exact knowledge of the immunopeptidome can directly fuel and guide the development of next-generation vaccines and immunotherapies against autoimmunity, infectious diseases, and cancers. In this mini-review, we summarize established isolation techniques as well as emerging mass spectrometry-based platforms (i.e. SWATH-MS) to identify and quantify MHC-associated peptides. We also highlight selected biological applications and discuss important current technical limitations that need to be solved to accelerate the development of this field. Molecular & Cellular

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Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

Caron

Kowalewski

Koh

et al. 2015

Molecular & Cellular Proteomics

198

118

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“…Vertebrates also express immunoproteasomes (IPs), in which the catalytic b-subunits are replaced by IFN-g-inducible homologs: LMP2 (aka b1i, Psmb9) for b1 (Psmb6), MECL1 (aka b2i, Psmb10) for b2 (Psmb7), and LMP7 (aka b5i, Psmb8) for b5 (Psmb5). The best-described nonredundant role ascribed to IPs is their enhanced ability to generate MHC class I-associated peptides (MIPs) (2)(3)(4)(5).…”

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“…Because CPs and IPs display distinct substrate preferences (4,17), we hypothesized that they might have nonredundant effects on gene expression. This assumption was supported by preliminary gene expression microarray experiments showing that several transcripts are differentially expressed in wild-type (WT) and IP-deficient dendritic cells (DCs) (4). The goal of our work was therefore to evaluate the global impact of IPs on gene expression, discover its underlying mechanisms, and evaluate its in vivo relevance.…”

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Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells

Verteuil

Rouette

Hardy

et al. 2014

The Journal of Immunology

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By regulating protein degradation, constitutive proteasomes (CPs) control practically all cellular functions. In addition to CPs, vertebrates express immunoproteasomes (IPs). The major nonredundant role ascribed to IPs is their enhanced ability to generate antigenic peptides. We report that CPs and IPs differentially regulate the expression of >8000 transcripts in maturing mouse dendritic cells (DCs) via regulation of signaling pathways such as IFN regulatory factors, STATs, and NF-κB. IPs regulate the transcription of many mRNAs and maturation of a few of them. Moreover, even when engineered to present optimal amounts of antigenic peptide, IP-deficient DCs are inefficient for in vivo T cell priming. Our study shows that the role of IPs in DCs is not limited to Ag processing and reveals a major nonredundant role for IPs in transcription regulation. The dramatic effect of IPs on the transcriptional landscape could explain the various immune and nonimmune phenotypes observed in vertebrates with IP deficiency or mutations.

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Proteasome isoforms exhibit only quantitative differences in cleavage and epitope generation

et al. 2014

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Immunoproteasomes are considered to be optimised to process Ags and to alter the peptide repertoire by generating a qualitatively different set of MHC class I epitopes. Whether the immunoproteasome at the biochemical level, influence the quality rather than the quantity of the immuno-genic peptide pool is still unclear. Here, we quantified the cleavage-site usage by human standard-and immunoproteasomes, and proteasomes from immuno-subunit-deficient mice, as well as the peptides generated from model polypeptides. We show in this study that the different proteasome isoforms can exert significant quantitative differences in the cleavage-site usage and MHC class I restricted epitope production. However, independent of the proteasome isoform and substrates studied, no evidence was obtained for the abolishment of the specific cleavage-site usage, or for differences in the quality of the peptides generated. Thus, we conclude that the observed differences in MHC class I restricted Ag presentation between standard-and immunoproteasomes are due to quantitative differences in the proteasome-generated antigenic peptides.Keywords: Antigen presentation r Immunoproteasome r MHC class I restricted epitopes r Proteasome r Proteolysis See accompanying Commentary by Zanker and ChenAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe 20S proteasome is the central proteolytic machinery of the ubiquitin proteasome system, being responsible for the main Correspondence: Dr. Michele Mishto e-mail: michele.mishto@charite.de part of extra-lysosomal protein degradation and generation of MHC class I restricted epitopes [1]. During evolution, the 20S proteasome retained a conserved structure of four stacked seven membered rings (α 7 β 7 β 7 α 7 ). In each β ring, the 20S standard proteasome has three catalytic standard subunits (i.e. β1s, β2s and β5s) that carry an N-terminal threonine residue as a reactive nucleophile. Based on the analysis of yeast 20S proteasome active site mutants with short fluorogenic peptide substrates C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 3508-3521 Antigen processing 3509 chymotryptic-, tryptic-and caspase-like activities were assigned to the β5, β2 and β1 subunits, respectively [2]. Larger polypeptide substrates bind with their residues surrounding the cleavage site, that is residues in position P4 to P1 (cleavage site) and P1 to P4 , to the non-primed and primed substrate binding sites [3] of the proteasome, respectively. This provides the stability and the orientation of the substrate, thereby determining the cleavage-site usage within a protein substrate [4]. In mammalia, the cytokine IFN-γ induces the expression of three active sites carrying alternative β1i/LMP2, β2i/MECL1 and β5i/LMP7 immuno-subunits, and in consequence the formation of the immunoproteasome isoforms [5].Since the β1i and β5i immuno-subunits are encoded within the MHC class II region in close neighbourhood to ...

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Deletion of Immunoproteasome Subunits Imprints on the Transcriptome and Has a Broad Impact on Peptides Presented by Major Histocompatibility Complex I molecules

Cited by 77 publications

References 61 publications

Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells

Proteasome isoforms exhibit only quantitative differences in cleavage and epitope generation

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