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Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex

Major histocompatibility complex class I (MHC I) molecules present antigenic peptides to cytotoxic T cells to eliminate infected or cancerous cells. The transporter associated with antigen processing (TAP) shuttles proteasomally generated peptides into the ER for MHC I loading. As central part of th...

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Autores principales: Sethumadhavan, Sunesh, Barth, Marie, Spaapen, Robbert M., Schmidt, Carla, Trowitzsch, Simon, Tampé, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795405/
https://www.ncbi.nlm.nih.gov/pubmed/35087068
http://dx.doi.org/10.1038/s41598-022-05000-9
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author Sethumadhavan, Sunesh
Barth, Marie
Spaapen, Robbert M.
Schmidt, Carla
Trowitzsch, Simon
Tampé, Robert
author_facet Sethumadhavan, Sunesh
Barth, Marie
Spaapen, Robbert M.
Schmidt, Carla
Trowitzsch, Simon
Tampé, Robert
author_sort Sethumadhavan, Sunesh
collection PubMed
description Major histocompatibility complex class I (MHC I) molecules present antigenic peptides to cytotoxic T cells to eliminate infected or cancerous cells. The transporter associated with antigen processing (TAP) shuttles proteasomally generated peptides into the ER for MHC I loading. As central part of the peptide-loading complex (PLC), TAP is targeted by viral factors, which inhibit peptide supply and thereby impact MHC I-mediated immune responses. However, it is still poorly understood how antigen presentation via different MHC I allotypes is affected by TAP inhibition. Here, we show that conditional expression of herpes simplex viral ICP47 suppresses surface presentation of HLA-A and HLA-C, but not of HLA-B, while the human cytomegaloviral US6 reduces surface levels of all MHC I allotypes. This marked difference in HLA-B antigen presentation is echoed by an enrichment of HLA-B allomorphs at US6-arrested PLC in comparison to ICP47-PLC. Although both viral factors prevent TAP-mediated peptide supply, our data imply that MHC I allomorphs favor different conformationally arrested states of the PLC, leading to differential downregulation of MHC I surface presentation. These findings will help understand MHC I biology in general and will even advance the targeted treatment of infections depending on patients’ allotypes.
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spelling pubmed-87954052022-01-28 Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex Sethumadhavan, Sunesh Barth, Marie Spaapen, Robbert M. Schmidt, Carla Trowitzsch, Simon Tampé, Robert Sci Rep Article Major histocompatibility complex class I (MHC I) molecules present antigenic peptides to cytotoxic T cells to eliminate infected or cancerous cells. The transporter associated with antigen processing (TAP) shuttles proteasomally generated peptides into the ER for MHC I loading. As central part of the peptide-loading complex (PLC), TAP is targeted by viral factors, which inhibit peptide supply and thereby impact MHC I-mediated immune responses. However, it is still poorly understood how antigen presentation via different MHC I allotypes is affected by TAP inhibition. Here, we show that conditional expression of herpes simplex viral ICP47 suppresses surface presentation of HLA-A and HLA-C, but not of HLA-B, while the human cytomegaloviral US6 reduces surface levels of all MHC I allotypes. This marked difference in HLA-B antigen presentation is echoed by an enrichment of HLA-B allomorphs at US6-arrested PLC in comparison to ICP47-PLC. Although both viral factors prevent TAP-mediated peptide supply, our data imply that MHC I allomorphs favor different conformationally arrested states of the PLC, leading to differential downregulation of MHC I surface presentation. These findings will help understand MHC I biology in general and will even advance the targeted treatment of infections depending on patients’ allotypes. Nature Publishing Group UK 2022-01-27 /pmc/articles/PMC8795405/ /pubmed/35087068 http://dx.doi.org/10.1038/s41598-022-05000-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sethumadhavan, Sunesh
Barth, Marie
Spaapen, Robbert M.
Schmidt, Carla
Trowitzsch, Simon
Tampé, Robert
Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title_full Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title_fullStr Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title_full_unstemmed Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title_short Viral immune evasins impact antigen presentation by allele-specific trapping of MHC I at the peptide-loading complex
title_sort viral immune evasins impact antigen presentation by allele-specific trapping of mhc i at the peptide-loading complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795405/
https://www.ncbi.nlm.nih.gov/pubmed/35087068
http://dx.doi.org/10.1038/s41598-022-05000-9
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