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HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes

Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal...

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Autores principales: Karnaukhov, Vadim, Paes, Wayne, Woodhouse, Isaac B., Partridge, Thomas, Nicastri, Annalisa, Brackenridge, Simon, Shcherbinin, Dmitrii, Chudakov, Dmitry M., Zvyagin, Ivan V., Ternette, Nicola, Koohy, Hashem, Borrow, Persephone, Shugay, Mikhail
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808399/
https://www.ncbi.nlm.nih.gov/pubmed/36605212
http://dx.doi.org/10.3389/fimmu.2022.1067463
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author Karnaukhov, Vadim
Paes, Wayne
Woodhouse, Isaac B.
Partridge, Thomas
Nicastri, Annalisa
Brackenridge, Simon
Shcherbinin, Dmitrii
Chudakov, Dmitry M.
Zvyagin, Ivan V.
Ternette, Nicola
Koohy, Hashem
Borrow, Persephone
Shugay, Mikhail
author_facet Karnaukhov, Vadim
Paes, Wayne
Woodhouse, Isaac B.
Partridge, Thomas
Nicastri, Annalisa
Brackenridge, Simon
Shcherbinin, Dmitrii
Chudakov, Dmitry M.
Zvyagin, Ivan V.
Ternette, Nicola
Koohy, Hashem
Borrow, Persephone
Shugay, Mikhail
author_sort Karnaukhov, Vadim
collection PubMed
description Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others – ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs.
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spelling pubmed-98083992023-01-04 HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes Karnaukhov, Vadim Paes, Wayne Woodhouse, Isaac B. Partridge, Thomas Nicastri, Annalisa Brackenridge, Simon Shcherbinin, Dmitrii Chudakov, Dmitry M. Zvyagin, Ivan V. Ternette, Nicola Koohy, Hashem Borrow, Persephone Shugay, Mikhail Front Immunol Immunology Human leukocyte antigen (HLA) genes are the most polymorphic loci in the human genome and code for proteins that play a key role in guiding adaptive immune responses by presenting foreign and self peptides (ligands) to T cells. Each person carries up to 6 HLA class I variants (maternal and paternal copies of HLA-A, HLA-B and HLA-C genes) and also multiple HLA class II variants, which cumulatively define the landscape of peptides presented to T cells. Each HLA variant has its own repertoire of presented peptides with a certain sequence motif which is mainly defined by peptide anchor residues (typically the second and the last positions for HLA class I ligands) forming key interactions with the peptide-binding groove of HLA. In this study, we aimed to characterize HLA binding preferences in terms of molecular functions of presented proteins. To focus on the ligand presentation bias introduced specifically by HLA-peptide interaction we performed large-scale in silico predictions of binding of all peptides from human proteome for a wide range of HLA variants and established which functions are characteristic for proteins that are more or less preferentially presented by different HLA variants using statistical calculations and gene ontology (GO) analysis. We demonstrated marked distinctions between HLA variants in molecular functions of preferentially presented proteins (e.g. some HLA variants preferentially present membrane and receptor proteins, while others – ribosomal and DNA-binding proteins) and reduced presentation of extracellular matrix and collagen proteins by the majority of HLA variants. To explain these observations we demonstrated that HLA preferentially presents proteins enriched in amino acids which are required as anchor residues for the particular HLA variant. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Taking into consideration that HLA alleles are inherited in haplotypes, we hypothesized that haplotypes composed of a combination of HLA variants with different presentation preferences should be more advantageous as they allow presenting a larger repertoire of peptides and avoiding holes in immunopeptidome. Indeed, we demonstrated that HLA-A/HLA-B and HLA-A/HLA-C haplotypes which have a high frequency in the human population are comprised of HLA variants that are more distinct in terms of functions of preferentially presented proteins than the control pairs. Frontiers Media S.A. 2022-12-20 /pmc/articles/PMC9808399/ /pubmed/36605212 http://dx.doi.org/10.3389/fimmu.2022.1067463 Text en Copyright © 2022 Karnaukhov, Paes, Woodhouse, Partridge, Nicastri, Brackenridge, Shcherbinin, Chudakov, Zvyagin, Ternette, Koohy, Borrow and Shugay https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Karnaukhov, Vadim
Paes, Wayne
Woodhouse, Isaac B.
Partridge, Thomas
Nicastri, Annalisa
Brackenridge, Simon
Shcherbinin, Dmitrii
Chudakov, Dmitry M.
Zvyagin, Ivan V.
Ternette, Nicola
Koohy, Hashem
Borrow, Persephone
Shugay, Mikhail
HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title_full HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title_fullStr HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title_full_unstemmed HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title_short HLA variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
title_sort hla variants have different preferences to present proteins with specific molecular functions which are complemented in frequent haplotypes
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808399/
https://www.ncbi.nlm.nih.gov/pubmed/36605212
http://dx.doi.org/10.3389/fimmu.2022.1067463
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