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A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behcet's disease in HLA-B*51 carriers.

ABSTRACT: INTRODUCTION:Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet's disease. METHODS:Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behçet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their contributions to Behçet's disease risk were determined by haplotype identification and disease association analyses. RESULTS:One ERAP1 protein allotype with five non-ancestral amino acids was recessively associated with disease (p=3.13×10-6, OR 2.55, 95% CI 1.70 to 3.82). The ERAP1 association was absent in individuals who lacked HLA-B*51. Individuals who carry HLA-B*51 and who are also homozygous for the haplotype had an increased disease odds compared with those with neither risk factor (p=4.80×10-20, OR 10.96, 95% CI 5.91 to 20.32). DISCUSSION:The Behçet's disease-associated ERAP1 protein allotype was previously shown to have poor peptide trimming activity. Combined with its requirement for HLA-B*51, these data suggest that a hypoactive ERAP1 allotype contributes to Behçet's disease risk by altering the peptides available for binding to HLA-B*51.

SUBMITTER: Takeuchi M

PROVIDER: S-EPMC5106293 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers.

Takeuchi Masaki M Ombrello Michael J MJ Kirino Yohei Y Erer Burak B Tugal-Tutkun Ilknur I Seyahi Emire E Özyazgan Yilmaz Y Watts Norman R NR Gül Ahmet A Kastner Daniel L DL Remmers Elaine F EF

Annals of the rheumatic diseases 20160523 12

<h4>Introduction</h4>Endoplasmic reticulum aminopeptidase-1 (ERAP1) protein is highly polymorphic with numerous missense amino acid variants. We sought to determine the naturally occurring ERAP1 protein allotypes and their contribution to Behçet's disease.<h4>Methods</h4>Genotypes of all reported missense ERAP1 gene variants with 1000 Genomes Project EUR superpopulation frequency >1% were determined in 1900 Behçet's disease cases and 1779 controls from Turkey. ERAP1 protein allotypes and their c ...[more]

PMID: 27217550

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Project description:Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behçet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ?). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ?40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

Dataset Information

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behcet's disease in HLA-B*51 carriers.

Publications

A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet's disease in HLA-B*51 carriers.

Similar Datasets

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