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

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.

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Effects of fumonisin B1 on HLA class I antigen presentation and processing pathway in GES-1 cells in vitro

Human & Experimental Toxicology ◽

10.1177/0960327110371812 ◽

2010 ◽

Vol 30 (5) ◽

pp. 379-390 ◽

Cited By ~ 2

Author(s):

ZG Yao ◽

XH Zhang ◽

F. Hua ◽

J. Wang ◽

X. Xing ◽

...

Keyword(s):

Antigen Presentation ◽

Heavy Chain ◽

Fumonisin B1 ◽

Hla Class I ◽

Class I ◽

International Agency ◽

Hla Class I Antigen ◽

Antigen Presentation Pathway ◽

Presentation Pathway

Fumonisin B1 (FB1) is a food-borne mycotoxin produced by genus Fusarium and was classified as possible carcinogen to humans by the International Agency for Research on Cancer (IARC). Human leukocyte antigen (HLA) class I antigen presentation pathway plays an important role in immunosurveillance. Defects in HLA class I antigen presentation pathway can down-regulate the expression of HLA class I antigen on the surface of nucleated cells that will confer a survival advantage to randomly mutant cells and may lead to malignant transformation. In the present study, we analyzed the effects of FB1 on the expression of HLA class I heavy chain (classical HLA-A, -B and -C genes included), beta2-microglobulin (β2m), LMP2 and TAP1 genes in human gastric epithelial immortalized GES-1 cells in vitro using semi-quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR), Western blot and immunocytochemical methods in dose- and time-effect studies. Our results revealed that FB1 have an effect on HLA class I antigen presentation pathway via the decreased expression of HLA class I heavy chain and/or defects of LMP2 and TAP1 expression. However, the importance of this effect in carcinogenesis needs further investigation.

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

eLife ◽

10.7554/elife.09617 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 44

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.

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LC3 and NLRC5 interaction inhibits NLRC5-mediated MHC class I antigen presentation pathway in endometrial cancer

Cancer Letters ◽

10.1016/j.canlet.2021.12.031 ◽

2021 ◽

Author(s):

Lei Zhan ◽

Junhui Zhang ◽

Jing Zhang ◽

Xiaojing Liu ◽

Suding Zhu ◽

...

Keyword(s):

Endometrial Cancer ◽

Antigen Presentation ◽

Mhc Class I ◽

Class I ◽

Antigen Presentation Pathway ◽

Presentation Pathway ◽

Mhc Class I Antigen

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

Journal of General Virology ◽

10.1099/vir.0.014746-0 ◽

2009 ◽

Vol 90 (12) ◽

pp. 2865-2870 ◽

Cited By ~ 25

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.

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Variations in MHC class I antigen presentation and immunopeptidome selection pathways

F1000Research ◽

10.12688/f1000research.26935.1 ◽

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.

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