scholarly journals Light control of the peptide-loading complex synchronizes antigen translocation and MHC I trafficking

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jamina Brunnberg ◽  
Valentina Herbring ◽  
Esteban Günther Castillo ◽  
Heike Krüger ◽  
Ralph Wieneke ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Antigen Processing ◽  
Adaptive Immune Response ◽  
Class I Mhc ◽  
Mhc I ◽  
Atp Binding Site ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Cellular Pathways ◽  
Cancerous Cells

AbstractAntigen presentation via major histocompatibility complex class I (MHC I) molecules is essential to mount an adaptive immune response against pathogens and cancerous cells. To this end, the transporter associated with antigen processing (TAP) delivers snippets of the cellular proteome, resulting from proteasomal degradation, into the ER lumen. After peptide loading and editing by the peptide-loading complex (PLC), stable peptide-MHC I complexes are released for cell surface presentation. Since the process of MHC I trafficking is poorly defined, we established an approach to control antigen presentation by introduction of a photo-caged amino acid in the catalytic ATP-binding site of TAP. By optical control, we initiate TAP-dependent antigen translocation, thus providing new insights into TAP function within the PLC and MHC I trafficking in living cells. Moreover, this versatile approach has the potential to be applied in the study of other cellular pathways controlled by P-loop ATP/GTPases.

scholarly journals Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 158 ◽  
Author(s):  
Andy van Hateren ◽  
Alistair Bailey ◽  
Tim Elliott
Keyword(s):  
Quality Control ◽  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Class I ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Mhc Class I Molecules

We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation.

scholarly journals Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

2016 ◽  
Vol 113 (8) ◽  
pp. E1006-E1015 ◽  
Author(s):  
Giora I. Morozov ◽  
Huaying Zhao ◽  
Michael G. Mage ◽  
Lisa F. Boyd ◽  
Jiansheng Jiang ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Class I Mhc ◽  
Mhc I ◽  
X Ray ◽  
X Ray Scattering ◽  
Histocompatibility Complex ◽  
Self Tolerance ◽  
Peptide Loading

Peptide loading of major histocompatibility complex class I (MHC-I) molecules is central to antigen presentation, self-tolerance, and CD8+ T-cell activation. TAP binding protein, related (TAPBPR), a widely expressed tapasin homolog, is not part of the classical MHC-I peptide-loading complex (PLC). Using recombinant MHC-I molecules, we show that TAPBPR binds HLA-A*02:01 and several other MHC-I molecules that are either peptide-free or loaded with low-affinity peptides. Fluorescence polarization experiments establish that TAPBPR augments peptide binding by MHC-I. The TAPBPR/MHC-I interaction is reversed by specific peptides, related to their affinity. Mutational and small-angle X-ray scattering (SAXS) studies confirm the structural similarities of TAPBPR with tapasin. These results support a role of TAPBPR in stabilizing peptide-receptive conformation(s) of MHC-I, permitting peptide editing.

The ABCs of Immunology: Structure and Function of TAP, the Transporter Associated with Antigen Processing

Physiology ◽  
2004 ◽  
Vol 19 (4) ◽  
pp. 216-224 ◽  
Author(s):  
Rupert Abele ◽  
Robert Tampé
Keyword(s):  
Antigen Processing ◽  
Cytotoxic T Cells ◽  
Peptide Delivery ◽  
Structure And Function ◽  
Transformed Cells ◽  
Tumor Escape ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
And Function

The transporter associated with antigen processing (TAP) is essential for peptide delivery from the cytosol into the lumen of the endoplasmic reticulum (ER), where these peptides are loaded on major histocompatibility complex (MHC) I molecules. Loaded MHC I leave the ER and display their antigenic cargo on the cell surface to cytotoxic T cells. Subsequently, virus-infected or malignantly transformed cells can be eliminated. Here we discuss the structure, function, and mechanism of TAP as a central part of the peptide-loading complex. Furthermore, aspects of virus and tumor escape strategies are presented.

DC-SIGN promotes exogenous MHC-I–restricted HIV-1 antigen presentation

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2648-2654 ◽  
Author(s):  
Arnaud Moris ◽  
Cinzia Nobile ◽  
Florence Buseyne ◽  
Françoise Porrot ◽  
Jean-Pierre Abastado ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Cytotoxic T Lymphocytes ◽  
Viral Envelope ◽  
Class I Mhc ◽  
Mhc I ◽  
High Affinity ◽  
Histocompatibility Complex ◽  
Anti Hiv ◽  
Hiv 1

Abstract Dendritic cells (DCs) facilitate HIV-1 spread in the host by capturing virions and transferring them to permissive lymphocytes in lymphoid organs. Lectins such as DC-specific ICAM-grabbing non-integrin (DC-SIGN) are involved in HIV-1 uptake by DCs, through high-affinity binding to viral envelope glycoproteins. We examined the role of DC-SIGN on the fate of incoming virions and on major histocompatibility complex class I (MHC-I)–restricted HIV-1 antigen presentation. We show that DC-SIGN expression in B-cell lines dramatically enhances viral internalization. In these cells, and also in primary DCs, most of the captured virions are rapidly degraded, likely in a lysosomal compartment. In addition, a fraction of incoming viral material is processed by the proteasome, leading to activation of anti–HIV-specific cytotoxic T lymphocytes (CTLs) by DC-SIGN–expressing cells. In DCs, DC-SIGN is not the only receptor involved, and redundant pathways of virus capture leading to antigen presentation likely coexist. Altogether, our results highlight new aspects of DC-SIGN interactions with HIV-1. The lectin does not significantly protect captured virions against degradation and promotes MHC-I exogenous presentation of HIV-1 antigens.

Ligand Design for Specific MHC Class I Molecules on the Cell Surface

2020 ◽  
Author(s):  
Xizheng Sun ◽  
Reika Tokunaga ◽  
Yoko Nagai ◽  
Ryo Miyahara ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Targeted Delivery ◽  
Peptide Ligands ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
High Binding Affinity ◽  
Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

scholarly journals Bovine papillomavirus type 1 oncoprotein E5 inhibits equine MHC class I and interacts with equine MHC I heavy chain

2009 ◽  
Vol 90 (12) ◽  
pp. 2865-2870 ◽  
Author(s):  
Barbara Marchetti ◽  
Elisabeth A. Gault ◽  
Marc S. Cortese ◽  
ZhengQiang Yuan ◽  
Shirley A. Ellis ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Class I ◽  
Bovine Papillomavirus ◽  
Class I Mhc ◽  
Mhc I ◽  
Reading Frame ◽  
Histocompatibility Complex ◽  
Human Telomerase

Bovine papillomavirus type 1 is one of the aetiological agents of equine sarcoids. The viral major oncoprotein E5 is expressed in virtually all sarcoids, sarcoid cell lines and in vitro-transformed equine fibroblasts. To ascertain whether E5 behaves in equine cells as it does in bovine cells, we introduced the E5 open reading frame into fetal equine fibroblasts (EqPalF). As observed in primary bovine fibroblasts (BoPalF), E5 by itself could not immortalize EqPalF and an immortalizing gene, such as human telomerase (hTERT/hT), was required for the cells to survive selection. The EqPalF-hT-1E5 cells were morphologically transformed, elongated with many pseudopodia and capable of forming foci. Equine major histocompatibility complex class I (MHC I) was inhibited in these cells at least at two levels: transcription of MHC I heavy chain was inhibited and the MHC I complex was retained in the Golgi apparatus and prevented from reaching the cell surface. We conclude that, as in bovine cells and tumours, E5 is a player in the transformation of equine cells and the induction of sarcoids, and a potential major cause of MHC I downregulation and hence poor immune clearance of tumour cells.

scholarly journals Alternative Endogenous Protein Processing via an Autophagy-Dependent Pathway Compensates for Yersinia-Mediated Inhibition of Endosomal Major Histocompatibility Complex Class II Antigen Presentation

2010 ◽  
Vol 78 (12) ◽  
pp. 5138-5150 ◽  
Author(s):  
Holger Rüssmann ◽  
Klaus Panthel ◽  
Brigitte Köhn ◽  
Stefan Jellbauer ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Virulence Factors ◽  
Antigen Processing ◽  
Class Ii ◽  
T Cell Response ◽  
Histocompatibility Complex ◽  
Class Ii Antigen ◽  
Mhc Class Ii Antigen

ABSTRACT Extracellular Yersinia pseudotuberculosis employs a type III secretion system (T3SS) for translocating virulence factors (Yersinia outer proteins [Yops]) directly into the cytosol of eukaryotic cells. Recently, we used YopE as a carrier molecule for T3SS-dependent secretion and translocation of listeriolysin O (LLO) from Listeria monocytogenes. We demonstrated that translocation of chimeric YopE/LLO into the cytosol of macrophages by Yersinia results in the induction of a codominant antigen-specific CD4 and CD8 T-cell response in orally immunized mice. In this study, we addressed the requirements for processing and major histocompatibility complex (MHC) class II presentation of chimeric YopE proteins translocated into the cytosol of macrophages by the Yersinia T3SS. Our data demonstrate the ability of Yersinia to counteract exogenous MHC class II antigen presentation of secreted hybrid YopE by the action of wild-type YopE and YopH. In the absence of exogenous MHC class II antigen presentation, an alternative pathway was identified for YopE fusion proteins originating in the cytosol. This endogenous antigen-processing pathway was sensitive to inhibitors of phagolysosomal acidification and macroautophagy, but it did not require the function either of the proteasome or of transporters associated with antigen processing. Thus, by an autophagy-dependent mechanism, macrophages are able to compensate for the YopE/YopH-mediated inhibition of the endosomal MHC class II antigen presentation pathway for exogenous antigens. This is the first report demonstrating that autophagy might enable the host to mount an MHC class II-restricted CD4 T-cell response against translocated bacterial virulence factors. We provide critical new insights into the interaction between the mammalian immune system and a human pathogen.

scholarly journals Variations in MHC class I antigen presentation and immunopeptidome selection pathways

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1177
Author(s):  
Anita J. Zaitouna ◽  
Amanpreet Kaur ◽  
Malini Raghavan
Keyword(s):  
Cell Surface ◽  
Antigen Presentation ◽  
Surface Expression ◽  
Structural Features ◽  
Class I ◽  
Cell Surface Expression ◽  
Immune Recognition ◽  
Antigen Receptors ◽  
Class I Mhc ◽  
Mhc I

Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

scholarly journals Transmembrane Helices Are an Over-Presented and Evolutionarily Conserved Source of Major Histocompatibility Complex Class I and II Epitopes

2022 ◽  
Vol 12 ◽  
Author(s):  
Richèl J. C. Bilderbeek ◽  
Maksim V. Baranov ◽  
Geert van den Bogaart ◽  
Frans Bianchi
Keyword(s):  
T Cell ◽  
Membrane Proteins ◽  
T Cell Responses ◽  
Class I ◽  
Complex Class ◽  
Transmembrane Helices ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most alleles of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefore peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the predicted over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II, and confirmed by re-analysis of epitope databases. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells are more tuned to respond to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs are less prone to mutations that enable pathogens to evade T cell responses.

scholarly journals Transmembrane helices are an overlooked and evolutionarily conserved source of major histocompatibility complex class II epitopes

2021 ◽  
Author(s):  
Richel Bilderbeek ◽  
Maksim Baranov ◽  
Frans Bianchi ◽  
Geert van den Bogaart
Keyword(s):  
T Cell ◽  
Membrane Proteins ◽  
T Cell Responses ◽  
Nucleotide Polymorphisms ◽  
Complex Class ◽  
Transmembrane Helices ◽  
Class I Mhc ◽  
Mhc I ◽  
Cell Responses ◽  
Histocompatibility Complex

Cytolytic T cell responses are predicted to be biased towards membrane proteins. The peptide-binding grooves of most haplotypes of histocompatibility complex class I (MHC-I) are relatively hydrophobic, therefor peptide fragments derived from human transmembrane helices (TMHs) are predicted to be presented more often as would be expected based on their abundance in the proteome. However, the physiological reason of why membrane proteins might be over-presented is unclear. In this study, we show that the over-presentation of TMH-derived peptides is general, as it is predicted for bacteria and viruses and for both MHC-I and MHC-II. Moreover, we show that TMHs are evolutionarily more conserved, because single nucleotide polymorphisms (SNPs) are present relatively less frequently in TMH-coding chromosomal regions compared to regions coding for extracellular and cytoplasmic protein regions. Thus, our findings suggest that both cytolytic and helper T cells respond more to membrane proteins, because these are evolutionary more conserved. We speculate that TMHs therefor are less prone to escape mutations that enable pathogens to evade T cell responses.

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