The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation
The monomorphic antigen-presenting molecule MHC-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 non-communicable diseases, and recent studies have begun to develop...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2021
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| _version_ | 1797107243608440832 |
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| author | Kulicke, CA De Zan, E Hein, Z Gonzalez-Lopez, C Ghanwat, S Veerapen, N Besra, GS Klenerman, P Christianson, JC Springer, S Nijman, S Cerundolo, V Salio, M |
| author_facet | Kulicke, CA De Zan, E Hein, Z Gonzalez-Lopez, C Ghanwat, S Veerapen, N Besra, GS Klenerman, P Christianson, JC Springer, S Nijman, S Cerundolo, V Salio, M |
| author_sort | Kulicke, CA |
| collection | OXFORD |
| description | The monomorphic antigen-presenting molecule MHC-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 non-communicable 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 β2-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 knock-out 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 post-transcriptional determinant of MR1 surface expression. |
| first_indexed | 2024-03-07T07:11:45Z |
| format | Journal article |
| id | oxford-uuid:158ef38c-eed6-40ce-9606-a7dad6b3ee9a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:11:45Z |
| publishDate | 2021 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:158ef38c-eed6-40ce-9606-a7dad6b3ee9a2022-07-12T11:19:29ZThe P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:158ef38c-eed6-40ce-9606-a7dad6b3ee9aEnglishSymplectic ElementsElsevier2021Kulicke, CADe Zan, EHein, ZGonzalez-Lopez, CGhanwat, SVeerapen, NBesra, GSKlenerman, PChristianson, JCSpringer, SNijman, SCerundolo, VSalio, MThe monomorphic antigen-presenting molecule MHC-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 non-communicable 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 β2-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 knock-out 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 post-transcriptional determinant of MR1 surface expression. |
| spellingShingle | Kulicke, CA De Zan, E Hein, Z Gonzalez-Lopez, C Ghanwat, S Veerapen, N Besra, GS Klenerman, P Christianson, JC Springer, S Nijman, S Cerundolo, V Salio, M 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 |
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