Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure
Ubiquitination is a process that dictates the lifespan of major histocompatibility complex class II (MHC II)/peptide complexes on antigen-presenting cells. This process is tightly controlled by the levels of ubiquitin ligases, and disruptions in the turnover of MHC II can lead to the improper develo...
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| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/23/17083 |
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| author | Yuko Kozono Masahiro Kuramochi Yuji C. Sasaki Haruo Kozono |
| author_facet | Yuko Kozono Masahiro Kuramochi Yuji C. Sasaki Haruo Kozono |
| author_sort | Yuko Kozono |
| collection | DOAJ |
| description | Ubiquitination is a process that dictates the lifespan of major histocompatibility complex class II (MHC II)/peptide complexes on antigen-presenting cells. This process is tightly controlled by the levels of ubiquitin ligases, and disruptions in the turnover of MHC II can lead to the improper development of CD4+ T cells within the thymus and hinder the formation of regulatory T cells in the peripheral tissue. To investigate the underlying mechanisms, we utilized dendritic cells lacking the Membrane-associated RING-CH (MARCH) I ubiquitin ligase. We discovered that the overexpression of MARCH I decreases the interaction with LAG-3. Moreover, the MHC II molecules tethered with ubiquitin also showed diminished binding to LAG-3. We employed Diffracted X-ray Blinking (DXB), a technique used for single-molecule X-ray imaging, to observe the protein movements on live cells in real time. Our observations indicated that the normal MHC II molecules moved more rapidly across the cell surface compared to those on the MARCH I-deficient dendritic cells or MHC II KR mutants, which is likely a result of ubiquitination. These findings suggest that the signaling from ubiquitinated MHC II to the T cell receptor differs from the non-ubiquitinated forms. It appears that ubiquitinated MHC II might not be quickly internalized, but rather presents antigens to the T cells, leading to a range of significant immunological responses. |
| first_indexed | 2024-03-09T01:49:00Z |
| format | Article |
| id | doaj.art-854d8be8dfa749779fd6608d7296d52a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T01:49:00Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-854d8be8dfa749779fd6608d7296d52a2023-12-08T15:18:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124231708310.3390/ijms242317083Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition StructureYuko Kozono0Masahiro Kuramochi1Yuji C. Sasaki2Haruo Kozono3Research Institute for Biomedical Sciences, Tokyo University of Sciences, Noda 278-0022, Chiba, JapanGraduate School of Science and Engineering, Ibaraki University, Hitachi 316-0033, Ibaraki, JapanDepartment of Advanced Material Science, Graduate School for Frontier Sciences, The University of Tokyo, Kashiwa 277-8568, Chiba, JapanResearch Institute for Biomedical Sciences, Tokyo University of Sciences, Noda 278-0022, Chiba, JapanUbiquitination is a process that dictates the lifespan of major histocompatibility complex class II (MHC II)/peptide complexes on antigen-presenting cells. This process is tightly controlled by the levels of ubiquitin ligases, and disruptions in the turnover of MHC II can lead to the improper development of CD4+ T cells within the thymus and hinder the formation of regulatory T cells in the peripheral tissue. To investigate the underlying mechanisms, we utilized dendritic cells lacking the Membrane-associated RING-CH (MARCH) I ubiquitin ligase. We discovered that the overexpression of MARCH I decreases the interaction with LAG-3. Moreover, the MHC II molecules tethered with ubiquitin also showed diminished binding to LAG-3. We employed Diffracted X-ray Blinking (DXB), a technique used for single-molecule X-ray imaging, to observe the protein movements on live cells in real time. Our observations indicated that the normal MHC II molecules moved more rapidly across the cell surface compared to those on the MARCH I-deficient dendritic cells or MHC II KR mutants, which is likely a result of ubiquitination. These findings suggest that the signaling from ubiquitinated MHC II to the T cell receptor differs from the non-ubiquitinated forms. It appears that ubiquitinated MHC II might not be quickly internalized, but rather presents antigens to the T cells, leading to a range of significant immunological responses.https://www.mdpi.com/1422-0067/24/23/17083ubiquitin ligaseMHCdendritic cellsLAG-3single-molecule biophysics |
| spellingShingle | Yuko Kozono Masahiro Kuramochi Yuji C. Sasaki Haruo Kozono Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure International Journal of Molecular Sciences ubiquitin ligase MHC dendritic cells LAG-3 single-molecule biophysics |
| title | Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure |
| title_full | Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure |
| title_fullStr | Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure |
| title_full_unstemmed | Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure |
| title_short | Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure |
| title_sort | ubiquitination of major histocompatibility complex ii changes its immunological recognition structure |
| topic | ubiquitin ligase MHC dendritic cells LAG-3 single-molecule biophysics |
| url | https://www.mdpi.com/1422-0067/24/23/17083 |
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