Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
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
_version_ 1784643829973909504
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
work_keys_str_mv AT kulickecorinnaa thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT dezanerica thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT heinzeynep thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT gonzalezlopezclaudia thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT ghanwatswapnil thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT veerapennatacha thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT besragurdyals thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT klenermanpaul thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT christiansonjohnc thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT springersebastian thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT nijmansebastianm thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT cerundolovincenzo thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT saliomariolina thep5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT kulickecorinnaa p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT dezanerica p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT heinzeynep p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT gonzalezlopezclaudia p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT ghanwatswapnil p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT veerapennatacha p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT besragurdyals p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT klenermanpaul p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT christiansonjohnc p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT springersebastian p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT nijmansebastianm p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT cerundolovincenzo p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation
AT saliomariolina p5typeatpaseatp13a1modulatesmajorhistocompatibilitycomplexirelatedprotein1mr1mediatedantigenpresentation