scholarly journals TAPBPR alters MHC class I peptide presentation by functioning as a peptide exchange catalyst

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Clemens Hermann ◽  
Andy van Hateren ◽  
Nico Trautwein ◽  
Andreas Neerincx ◽  
Patrick J Duriez ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Class I ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Peptide Presentation ◽  
Peptide Exchange ◽  
Specific Peptide

Our understanding of the antigen presentation pathway has recently been enhanced with the identification that the tapasin-related protein TAPBPR is a second major histocompatibility complex (MHC) class I-specific chaperone. We sought to determine whether, like tapasin, TAPBPR can also influence MHC class I peptide selection by functioning as a peptide exchange catalyst. We show that TAPBPR can catalyse the dissociation of peptides from peptide-MHC I complexes, enhance the loading of peptide-receptive MHC I molecules, and discriminate between peptides based on affinity in vitro. In cells, the depletion of TAPBPR increased the diversity of peptides presented on MHC I molecules, suggesting that TAPBPR is involved in restricting peptide presentation. Our results suggest TAPBPR binds to MHC I in a peptide-receptive state and, like tapasin, works to enhance peptide optimisation. It is now clear there are two MHC class I specific peptide editors, tapasin and TAPBPR, intimately involved in controlling peptide presentation to the immune system.

scholarly journals LC3 and NLRC5 Interaction Inhibits NLRC5-Mediated MHC Class I Antigen Presentation Pathway in Endometrial Cancer

2021 ◽  
Author(s):  
Lei Zhan ◽  
Junhui Zhang ◽  
Jing Zhang ◽  
Xiaojing Liu ◽  
Suding Zhu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Antigen Presentation ◽  
Class I ◽  
Normal Endometrium ◽  
Tumor Immune Escape ◽  
Class I Mhc ◽  
Mhc I ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway

Abstract Background: The major histocompatibility complex class I (MHC- I) transactivator, nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 5 (NLRC5), serves as a target for immune evasion in many cancers, including endometrial cancer (EC). An inhibition of autophagy can contribute to immunotherapy by assisting the MHC-I-mediated antigen presentation in cancer. However, the underlying mechanism for autophagy-regulated MHC-I in EC remains unclear. Our study aimed to investigate the effect of autophagy on NLRC5 and MHC-I-mediated antigen presentation, and to identify the potential mechanisms underlying this process in EC.Methods: We examined the levels of autophagy and MHC-I genes by performing transmission electron microscopy (TEM), RNA-seq sequencing, western blotting, and qRT-PCR. The t-test, F-test, Kaplan-Meier analysis, and Pearson’s correlation analysis were used for statistical evaluations of tissue microarrays. Immunofluorescence staining, co-immunoprecipitation (CO-IP), and glutathione S-transferase (GST) pull-down assay were performed. HEC-1A, AN3CA, and Ishikawa EC cells were transfected designed, and the role of LC3 and NLRC5 in MHC-I-mediated antigen presentation in EC was further evaluated in a xenotransplantation model of HEC-1A cell line. Results: Autophagy was upregulated in EC endometrium as compared to that in normal endometrium. MHC I and NLRC5 expressions were lower in EC endometrium than in normal endometrium. Autophagy played a negative role in the MHC-I genes expression in vitro. Furthermore, a negative correlation was found between LC3 and NLRC5 levels, and LC3 interacted with NLRC5 to inhibit NLRC5-mediated MHC-I antigen presentation pathway in vitro and in vivo. Conclusion: An upregulation of LC3 in EC patients may contribute to tumor immune escape by restricting the NLRC5-mediated MHC-I antigen presentation pathway, suggesting that inhibiting LC3 and promoting NLRC5 may be a promising immunotherapy strategy in the management of EC.

scholarly journals TAPBPR bridges UDP-glucose:glycoprotein glucosyltransferase 1 onto MHC class I to provide quality control in the antigen presentation pathway

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Andreas Neerincx ◽  
Clemens Hermann ◽  
Robin Antrobus ◽  
Andy van Hateren ◽  
Huan Cao ◽  
...  
Keyword(s):  
Quality Control ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Class I ◽  
Antigen Presentation Pathway ◽  
Multimeric Complex ◽  
Presentation Pathway ◽  
Peptide Loading ◽  
Peptide Exchange ◽  
Mhc Class I Molecules

Recently, we revealed that TAPBPR is a peptide exchange catalyst that is important for optimal peptide selection by MHC class I molecules. Here, we asked whether any other co-factors associate with TAPBPR, which would explain its effect on peptide selection. We identify an interaction between TAPBPR and UDP-glucose:glycoprotein glucosyltransferase 1 (UGT1), a folding sensor in the calnexin/calreticulin quality control cycle that is known to regenerate the Glc1Man9GlcNAc2 moiety on glycoproteins. Our results suggest the formation of a multimeric complex, dependent on a conserved cysteine at position 94 in TAPBPR, in which TAPBPR promotes the association of UGT1 with peptide-receptive MHC class I molecules. We reveal that the interaction between TAPBPR and UGT1 facilities the reglucosylation of the glycan on MHC class I molecules, promoting their recognition by calreticulin. Our results suggest that in addition to being a peptide editor, TAPBPR improves peptide optimisation by promoting peptide-receptive MHC class I molecules to associate with the peptide-loading complex.

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 TAPBPR mediates peptide dissociation from MHC class I using a leucine lever

2018 ◽  
Author(s):  
F. Tudor Ilca ◽  
Andreas Neerincx ◽  
Clemens Hermann ◽  
Ana Marcu ◽  
Stefan Stevanovic ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Dependent Manner ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Dissociation ◽  
Peptide Exchange

AbstractTapasin and TAPBPR are known to perform peptide editing on major histocompatibility complex class I (MHC I) molecules, however, the precise molecular mechanism(s) involved in this process remain largely enigmatic. Here, using immunopeptidomics in combination with novel cell-based assays that assess TAPBPR-mediate peptide exchange, we reveal a critical role for the K22-D35 loop of TAPBPR in mediating peptide exchange on MHC I. We identify a specific leucine within this loop that enables TAPBPR to facilitate peptide dissociation from MHC I. Moreover, we delineate the molecular features of the MHC I F pocket required for TAPBPR to promote peptide dissociation in a loop-dependent manner. These data reveal that chaperone-mediated peptide editing of MHC I can occur by different mechanisms dependent on the C-terminal residue that the MHC I accommodates in its F pocket and provide novel insights that may inform the therapeutic potential of TAPBPR manipulation to increase tumour immunogenicity.Impact StatementThis work demonstrates for the first time that the K22-D35 loop of TAPBPR is the essential region for mediating peptide exchange and peptide selection on major histocompatibility complex class I molecules.

scholarly journals The MHC class I peptide repertoire is molded by the transcriptome

2008 ◽  
Vol 205 (3) ◽  
pp. 595-610 ◽  
Author(s):  
Marie-Hélène Fortier ◽  
Étienne Caron ◽  
Marie-Pierre Hardy ◽  
Grégory Voisin ◽  
Sébastien Lemieux ◽  
...  
Keyword(s):  
Mhc Class I ◽  
High Throughput ◽  
Class I ◽  
High Throughput Analysis ◽  
Mhc I ◽  
Cyclin Dependent Kinases ◽  
Histocompatibility Complex ◽  
Accurate Definition ◽  
Primary Mouse ◽  
Definition Of

Under steady-state conditions, major histocompatibility complex (MHC) I molecules are associated with self-peptides that are collectively referred to as the MHC class I peptide (MIP) repertoire. Very little is known about the genesis and molecular composition of the MIP repertoire. We developed a novel high-throughput mass spectrometry approach that yields an accurate definition of the nature and relative abundance of unlabeled peptides presented by MHC I molecules. We identified 189 and 196 MHC I–associated peptides from normal and neoplastic mouse thymocytes, respectively. By integrating our peptidomic data with global profiling of the transcriptome, we reached two conclusions. The MIP repertoire of primary mouse thymocytes is biased toward peptides derived from highly abundant transcripts and is enriched in peptides derived from cyclins/cyclin-dependent kinases and helicases. Furthermore, we found that ∼25% of MHC I–associated peptides were differentially expressed on normal versus neoplastic thymocytes. Approximately half of those peptides are derived from molecules directly implicated in neoplastic transformation (e.g., components of the PI3K–AKT–mTOR pathway). In most cases, overexpression of MHC I peptides on cancer cells entailed posttranscriptional mechanisms. Our results show that high-throughput analysis and sequencing of MHC I–associated peptides yields unique insights into the genesis of the MIP repertoire in normal and neoplastic cells.

Deficient MHC class I cross-presentation of soluble antigen by murine neonatal dendritic cells

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4240-4242 ◽  
Author(s):  
Tobias R. Kollmann ◽  
Sing Sing Way ◽  
Heidi L. Harowicz ◽  
Adeline M. Hajjar ◽  
Christopher B. Wilson
Keyword(s):  
Dendritic Cells ◽  
Mhc Class I ◽  
T Cell Response ◽  
Class I ◽  
Soluble Antigen ◽  
In Vitro System ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Large Numbers

Abstract Neonates respond suboptimally to many vaccines. The reasons for this defect are unclear, but suboptimal antigen presentation by dendritic cells has been suggested as one possibility. In this report we describe an in vitro system that allows the generation of large numbers of resting murine neonatal dendritic cells facilitating their study. Using this system, we show a clear reduction in the ability of neonatal dendritic cells to present soluble ovalbumin, while the capacity to present ovalbumin peptide is intact. This suggests a specific defect in cross-presentation of exogenous antigen via the major histocompatibility complex (MHC) class I pathway. Deficient cross-presentation may contribute to the suboptimal CD8 T-cell response to vaccines in neonates. (Blood. 2004;103:4240-4242)

Identifying novel ubiquitin E3 ligases in the MHC class I antigen presentation pathway

2012 ◽  
Vol 51 (1) ◽  
pp. 21
Author(s):  
Paul Lehner ◽  
Florencia Cano ◽  
Marian Burr ◽  
Richard Timms ◽  
Jessica Boname ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class I ◽  
Class I ◽  
E3 Ligases ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway ◽  
Mhc Class I Antigen
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