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The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation
The monomorphic antigen-presenting molecule major histocompatibility complex-I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and noncommunicable diseases, and recent st...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808182/ https://www.ncbi.nlm.nih.gov/pubmed/34968463 http://dx.doi.org/10.1016/j.jbc.2021.101542 |
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author | Kulicke, Corinna A. De Zan, Erica Hein, Zeynep Gonzalez-Lopez, Claudia Ghanwat, Swapnil Veerapen, Natacha Besra, Gurdyal S. Klenerman, Paul Christianson, John C. Springer, Sebastian Nijman, Sebastian M. Cerundolo, Vincenzo Salio, Mariolina |
author_facet | Kulicke, Corinna A. De Zan, Erica Hein, Zeynep Gonzalez-Lopez, Claudia Ghanwat, Swapnil Veerapen, Natacha Besra, Gurdyal S. Klenerman, Paul Christianson, John C. Springer, Sebastian Nijman, Sebastian M. Cerundolo, Vincenzo Salio, Mariolina |
author_sort | Kulicke, Corinna A. |
collection | PubMed |
description | The monomorphic antigen-presenting molecule major histocompatibility complex-I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and noncommunicable diseases, and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialized antigen presentation pathway. However, proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β(2)-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-type ATPase in the endoplasmic reticulum (ER) not previously known to be associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knockout of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 being a key posttranscriptional determinant of MR1 surface expression. |
format | Online Article Text |
id | pubmed-8808182 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-88081822022-02-08 The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation Kulicke, Corinna A. De Zan, Erica Hein, Zeynep Gonzalez-Lopez, Claudia Ghanwat, Swapnil Veerapen, Natacha Besra, Gurdyal S. Klenerman, Paul Christianson, John C. Springer, Sebastian Nijman, Sebastian M. Cerundolo, Vincenzo Salio, Mariolina J Biol Chem Research Article The monomorphic antigen-presenting molecule major histocompatibility complex-I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and noncommunicable diseases, and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialized antigen presentation pathway. However, proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β(2)-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-type ATPase in the endoplasmic reticulum (ER) not previously known to be associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knockout of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 being a key posttranscriptional determinant of MR1 surface expression. American Society for Biochemistry and Molecular Biology 2021-12-27 /pmc/articles/PMC8808182/ /pubmed/34968463 http://dx.doi.org/10.1016/j.jbc.2021.101542 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Kulicke, Corinna A. De Zan, Erica Hein, Zeynep Gonzalez-Lopez, Claudia Ghanwat, Swapnil Veerapen, Natacha Besra, Gurdyal S. Klenerman, Paul Christianson, John C. Springer, Sebastian Nijman, Sebastian M. Cerundolo, Vincenzo Salio, Mariolina The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title | The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title_full | The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title_fullStr | The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title_full_unstemmed | The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title_short | The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation |
title_sort | p5-type atpase atp13a1 modulates major histocompatibility complex i-related protein 1 (mr1)-mediated antigen presentation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808182/ https://www.ncbi.nlm.nih.gov/pubmed/34968463 http://dx.doi.org/10.1016/j.jbc.2021.101542 |
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