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Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

ABSTRACT: The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. Rapidly degraded nascent polypeptides (DRiPs) provide many class I peptide ligands. By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. We show that 60S ribosomal proteins L6 (RPL6) and RPL28, which are adjacent on the ribosome, play opposite roles in generating an influenza A virus encoded peptide. RPL6 depletion decreases ubiquitin-dependent peptide presentation, while RPL28 depletion increases ubiquitin-dependent and -independent peptide presentation. 40S ribosomal protein S28 (RPS28) knockdown increases total peptide supply in uninfected cells by increasing DRiP synthesis from non-canonical translation of “untranslated” regions and non-AUG start codons, and sensitizes tumor cells for T cell targeting. RPL23 knocKDut decreases overall peptide supply, impairing T cell recognition of tumor cells. Our findings raise the possibility of modulating immunosurveillance by pharmacologically targeting ribosomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114484 | GEO | 2019/01/21

REPOSITORIES: GEO

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Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

Project description:Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

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Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_GSK126]

Project description:Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well-defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.

2020-11-02 | GSE160609 | GEO

Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_RNAseq]

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Tuning DO:DM ratios modulates HLA class II immunopeptidomes

Project description:Major Histocompatibility Complex Class II antigen presentation underlies a wide range of immune responses in health and disease. Although peptide ligand binding affinity has been the major focus for explaining and predicting class II antigens, we know that the levels and activities of accessory molecules, HLA-DM (DM) and HLA-DO (DO) can have strong effects on peptide repertoires. However, the extent to which these antagonistic proteins’ levels relative to one another shape the identities and properties of peptides selected for presentation remains unclear. Hence, after creating cell line panel with varying DO:DM ratios, of we set out to measure the effects these ratios can have on peptide presentation. Using a combined immunopeptidomic and proteomic discovery strategy, we profiled ligandome differences across this panel. By surveying over 10,000 unique HLA-DR4-presented peptides, we found marked increases in repertoire diversity and altered physical properties of presented peptides that corresponded with increasing DO:DM ratios.

2023-10-24 | PXD024392 | Pride

Gene profilling of splenic CD4+ T cells from naïve H2-O Wildtype and H2-O Knockout mice

Project description:Loss of the MHC Class II accessory molecule H2-O has been shown to alter the peptide repertoir presented by MHC Class II molecules. Using scRNA-Seq we interrogated what outcomes altered antigen presentation was having on the naïve CD4 T cell milieu.

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Rapid CLIP Dissociation from MHC II Promotes an Unusual Antigen Presentation Pathway in Autoimmunity

Project description:A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes-associated b57 polymorphism. We generated knock-in Non-obese Diabetic (NOD) mice with a single amino acid change in the CLIP segment of invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within b cell secretory granules. Rapid CLIP dissociation enhanced presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

2018-08-09 | GSE118322 | GEO

Homo sapiens

Project description:Autophagy promotes MHC class II presentation of peptides from intracellular source proteins

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MHC peptides presentation is limited by availability of empty HLA molecules rather than the supply of peptides ligands

Project description:Whether the presentation levels of the major histocompatibility complex (MHC, called the human leukocytes antigens, HLA, in humans) is limited by the availability of peptide ligands for loading or by the supply of empty MHC molecules, is a yet unresolved issue. This study aims to tackle this dilemma using large-scale immunopeptidome analyses. First, cultured cells (MCF-7) were treated with interferons, which dramatically increased presentation levels of their HLA-B molecules, much more than HLA-A and HLA-C. The differential increase in the HLA-B molecules with their bound peptides, was driven by elevated HLA synthesis levels and not by supply of peptides, since all three HLA allotypes draw peptides from the same peptide pool, which should have been affected similarly by the interferons treatment. In addition, artificial competition for peptides was created by recombinant high levels expression of soluble HLA-A*02:01 molecules, in the same MCF-7 cells and on top of their endogenous membranal HLA-A*02:01. This high level expression of the soluble HLA did not affect the endogenous membranal HLA-A*02:01 peptidomes or its cell surface presentation levels. We therefore concluded that a surplus supply of peptides is available for loading and that presentation levels are more likely limited by the supply of HLA molecules.

2018-05-10 | PXD007596 | Pride

Viral immune evasions differentially impact cell surface presentation of MHC I allomorphs already at the peptide-loading complex

Project description:The transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the endoplasmic reticulum (ER) where they are loaded onto major histocompatibility class I (MHC I) molecules. Stable peptide-MHC I complexes travel to the cell surface and present their antigenic cargo to cytotoxic T lymphocytes. As central part of the peptide-loading complex (PLC), TAP is targeted by several viral proteins, which inhibit peptide translocation and thereby impact MHC I-mediated immune responses. However, it is still poorly understood whether the MHC I allotypes are differently affected by TAP inhibition. Here, we show that conditional expression of herpes simplex virus (HSV) ICP47 suppresses surface presentation of the MHC I allotypes HLA-A and HLA-C, but not of HLA-B, while expression of cytomegalovirus (CMV) US6 reduces surface levels of all allotypes. This difference is directly reflected in a specific enrichment of HLA-B molecules at US6 arrested PLC. Since ICP47 and US6 inhibit TAP in different transport-incompetent conformations, our data imply that MHC I allomorphs are preferentially recruited or trapped at the PLC leading to selective downregulation of MHC I surface presentation. Our findings suggest that viral immune evasions not only inhibit peptide supply to the ER by TAP, but also modulate the assembly and chaperone activity of the PLC.

2022-02-17 | PXD027408 | Pride

Quantitative Measurement of the Requirement of Diverse Protein Degradation Pathways in MHC Class I Peptide Presentation

Project description:The adaptive immune system distinguishes self from non-self by surveying peptides generated from degradation of intracellular proteins that are loaded onto MHC Class I molecules for display on the cell surface. While early studies reported that the bulk of cell surface MHC Class I complexes require the ubiquitin-proteasome system (UPS) for their generation, this conclusion has been challenged. To better understand MHC Class I peptide origins, we sought to carry out a comprehensive, quantitative census of the MHC Class I peptide repertoire in the presence and absence of UPS activity. We introduce optimized methodology to enrich for authentic Class I-bound peptides in silico and then quantify by mass spectrometry their relative amounts upon perturbation of the ubiquitin-proteasome system. Whereas most peptides are dependent on the proteasome and ubiquitination for their generation, a surprising 30% of the MHC Class I repertoire, enriched in peptides of mitochondrial origin, appears independent of these pathways. A further ~10% of Class I-bound peptides were found to be dependent on the proteasome but independent of ubiquitination for their generation. Notably, clinically achievable partial inhibition of the proteasome resulted in display of novel peptide antigens. Our results suggest that generation of MHC Class I/peptide complexes is more complex than previously recognized, with UPS-dependent and UPS-independent components; paradoxically, a smaller number of atypical peptides increase in presentation when canonical pathways are impaired. -------------------------------------------------------------------------------------------------------------Please see supplementary file S1.xlsx for a detailed file description.

2023-02-15 | MSV000091285 | MassIVE

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