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How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

ABSTRACT: Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

SUBMITTER: Lopez de Castro JA

PROVIDER: S-EPMC6219399 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

López de Castro José A JA

Frontiers in immunology 20181030

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume ...[more]

PMID: 30425713

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Project description:Single nucleotide polymorphisms (SNPs) in the endoplasmic reticulum aminopeptidase (ERAP1 and ERAP2) genes are associated with the pathogenesis of bacterial and viral infections. To search for the variations in the ERAP1 and ERAP2 genes associated with tuberculosis (TB), 449 TB cases and 435 healthy individuals of the Han population in the Yunnan province of China were included in the present study. Eleven SNPs of ERAPs were genotyped using the SNaPshot SNP assay. Allelic, genotypic, and haplotypic association analyses were performed between the TB and control groups. Furthermore, stratification analyses among pulmonary TB (PTB), extrapulmonary TB (EPTB), and healthy controls; and initial treatment TB (ITTB), retreatment TB (RTB), and healthy controls were also performed. The TT genotype of rs26618 in ERAP1 exhibited a protective factor for TB, compared with the role of the CC/CT genotype (P = 0.003; OR = 1.490, 95% CI: 1.140-1.940). In ERAP2, the frequency of the G allele of rs2549782 was higher in the case group than in the control group (0.491 vs. 0.417, P = 0.002, OR = 1.350, 95% CI: 1.118-1.631), and the TT genotype exhibited a protective factor for TB, compared with the role of the GG/GT genotype (P = 0.001; OR = 1.650, 95% CI: 1.230-2.220). The frequency of the C allele of rs1056893 was higher in the case group than in the control group (0.468 vs. 0.394, P = 0.002, OR = 1.350, 95% CI: 1.118-1.631), and the genotype exhibited a difference in the log-additive model (P = 0.002; OR = 1.350, 95% CI: 1.120-1.630). The frequencies of the haplotype rs27037-rs27044-s30187-rs26618-rs26653-rs3734016-GCCCGC in ERAP1 (0.290 vs. 0.240, P-adj = 0.028, OR = 1.320, 95% CI: 1.063-1.638) and the haplotypes rs2549782-rs2248374-rs2287988-rs1056893-GTAGC in ERAP2 (0.446 vs. 0.348, P-adj = 4.80E-05, OR = 1.510, 95% CI: 1.246-1.829) was higher in the TB groups, while the frequencies of the haplotypes rs2549782-rs2248374-rs2287988-rs1056893-TAGAT (0.478 vs. 0.539, P-adj = 0.020, OR = 0.782, 95% CI: 0.649-0.943) were lower in the TB groups. The allelic and genotypic associations were also investigated in the subsequent stratification between the PTB, EPTB and control groups as well as between the ITTB, RTB, and control groups. In conclusion, variations in ERAP1 and ERAP2 genes were identified to be associated with TB in the Han Chinese population.

Project description:Pre-eclampsia (PE) is a disorder of pregnancy, often leading to serious and fatal complications. Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1/ERAP2) are present in the placenta. They are involved in processes regulating blood pressure, angiogenesis, cytokine receptor shedding, and immune recognition. Previous studies have associated both ERAP1/ERAP2 genetic variants with PE, although the underlying mechanisms remain unknown. Less is known about the roles for these enzymes in early placentation, which could be a contributory factor to PE. To ascertain whether ERAP1/ERAP2 change in PE and whether such a change is present before PE is clinically diagnosed, we analyzed mRNA and ERAP1/2 protein expression in the placenta in the early first trimester (8-14 weeks) and at delivery in normotensive or PE women (n = 12/group). Gene expression was analyzed using qPCR, and protein expression and localization were assessed by immunohistochemistry. Additionally, we profiled peripheral immune cells from normotensive and PE (n = 5/group) women for activation and expression of cytotoxic markers using flow cytometry to investigate a possible correlation with placental expression of ERAP1/2. Finally, we characterized the cytokines released from immune cells isolated from normotensive women and those with PE, stimulated ex vivo by JEG-3 trophoblast cells. The ERAP1 protein was significantly upregulated in first trimester placentae compared to placentae at delivery from both normotensive and PE women (p < 0.05): expression of placental ERAP1 protein was also relatively higher in normotensive than PE women. Although the protein expression of both ERAP1/ERAP2 was significantly lower in women with PE compared to normotensive controls (p < 0.05), ERAP2 protein expression remained unchanged in normotensive women at delivery compared to expression in the first trimester. Flow cytometry analysis revealed an increase in activation and cytotoxic natural killer (NK) cells in peripheral blood of PE compared to normotensive women. Intriguingly, there was a notable difference in cytokine release from the activated immune cells when further stimulated by trophoblast cells. The immune cells from PE released elevated expressions of interleukin (IL)-2, IL-4, and most notably, pro-inflammatory IL-13 and IL-17?, inflammatory cytokines tumor necrosis factor (TNF)-? and interferon (IFN)-?, and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to normal peripheral blood mononuclear cells (PBMCs). Taken together, these findings suggest that differential lymphocyte activation could be associated with altered ERAP1/ERAP2 expression.

Dataset Information

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

Publications

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

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