Identification of an unconventional sub-peptidome bound to the Behçet's disease - associated HLA-B*51:01 that is regulated by endoplasmic reticulum aminopeptidase 1 (ERAP1).
Identifieur interne : 000171 ( PubMed/Corpus ); précédent : 000170; suivant : 000172Identification of an unconventional sub-peptidome bound to the Behçet's disease - associated HLA-B*51:01 that is regulated by endoplasmic reticulum aminopeptidase 1 (ERAP1).
Auteurs : Liye Chen ; Hui Shi ; Danai Koftori ; Takuya Sekine ; Annalisa Nicastri ; Nicola Ternette ; Paul BownessSource :
- Molecular & cellular proteomics : MCP [ 1535-9484 ] ; 2020.
Abstract
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 sub-peptidome, 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 Proline or Alanine at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared to the Pro2 and Ala2 sub-peptidomes, and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant Leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to approximately 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 sub-peptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.
DOI: 10.1074/mcp.RA119.001617
PubMed: 32161166
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pubmed:32161166Le document en format XML
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<author><name sortKey="Chen, Liye" sort="Chen, Liye" uniqKey="Chen L" first="Liye" last="Chen">Liye Chen</name>
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<author><name sortKey="Koftori, Danai" sort="Koftori, Danai" uniqKey="Koftori D" first="Danai" last="Koftori">Danai Koftori</name>
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<series><title level="j">Molecular & cellular proteomics : MCP</title>
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<front><div type="abstract" xml:lang="en">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 sub-peptidome, 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 Proline or Alanine at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared to the Pro2 and Ala2 sub-peptidomes, and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant Leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to approximately 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 sub-peptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.</div>
</front>
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<pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32161166</PMID>
<DateRevised><Year>2020</Year>
<Month>03</Month>
<Day>12</Day>
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<Day>11</Day>
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<Title>Molecular & cellular proteomics : MCP</Title>
<ISOAbbreviation>Mol. Cell Proteomics</ISOAbbreviation>
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<ArticleTitle>Identification of an unconventional sub-peptidome bound to the Behçet's disease - associated HLA-B*51:01 that is regulated by endoplasmic reticulum aminopeptidase 1 (ERAP1).</ArticleTitle>
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<Abstract><AbstractText>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 sub-peptidome, 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 Proline or Alanine at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared to the Pro2 and Ala2 sub-peptidomes, and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant Leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to approximately 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 sub-peptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.</AbstractText>
<CopyrightInformation>Published under license by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation>
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<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Liye</ForeName>
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<AffiliationInfo><Affiliation>Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom liyechen2009@gmail.com.</Affiliation>
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<Author ValidYN="Y"><LastName>Shi</LastName>
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<Author ValidYN="Y"><LastName>Koftori</LastName>
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<AffiliationInfo><Affiliation>Target Discovery Institute, University of Oxford, United Kingdom.</Affiliation>
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<Author ValidYN="Y"><LastName>Ternette</LastName>
<ForeName>Nicola</ForeName>
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<AffiliationInfo><Affiliation>Jenner Institute, University of Oxford, United Kingdom.</Affiliation>
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<Language>eng</Language>
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<ArticleDate DateType="Electronic"><Year>2020</Year>
<Month>03</Month>
<Day>11</Day>
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<MedlineTA>Mol Cell Proteomics</MedlineTA>
<NlmUniqueID>101125647</NlmUniqueID>
<ISSNLinking>1535-9476</ISSNLinking>
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<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Antigen presentation</Keyword>
<Keyword MajorTopicYN="N">Behçet's disease</Keyword>
<Keyword MajorTopicYN="N">ERAP1</Keyword>
<Keyword MajorTopicYN="N">HLA-B*51:01</Keyword>
<Keyword MajorTopicYN="N">Immunoaffinity</Keyword>
<Keyword MajorTopicYN="N">Immunology*</Keyword>
<Keyword MajorTopicYN="N">Immunopeptidome</Keyword>
<Keyword MajorTopicYN="N">Mass Spectrometry</Keyword>
<Keyword MajorTopicYN="N">Peptides*</Keyword>
<Keyword MajorTopicYN="N">Tandem Mass Spectrometry</Keyword>
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<Month>06</Month>
<Day>07</Day>
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<PubMedPubDate PubStatus="revised"><Year>2020</Year>
<Month>03</Month>
<Day>10</Day>
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<Month>3</Month>
<Day>13</Day>
<Hour>6</Hour>
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