SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells
Summary: Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8+ T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we repor...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723015188 |
| _version_ | 1797448771460661248 |
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| author | Conor M. Henry Carlos A. Castellanos Michael D. Buck Evangelos Giampazolias Bruno Frederico Ana Cardoso Neil C. Rogers Oliver Schulz Sonia Lee Johnathan Canton Peter Faull Ambrosius P. Snijders Bhopal Mohapatra Hamid Band Caetano Reis e Sousa |
| author_facet | Conor M. Henry Carlos A. Castellanos Michael D. Buck Evangelos Giampazolias Bruno Frederico Ana Cardoso Neil C. Rogers Oliver Schulz Sonia Lee Johnathan Canton Peter Faull Ambrosius P. Snijders Bhopal Mohapatra Hamid Band Caetano Reis e Sousa |
| author_sort | Conor M. Henry |
| collection | DOAJ |
| description | Summary: Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8+ T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8+ T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity. |
| first_indexed | 2024-03-09T14:15:17Z |
| format | Article |
| id | doaj.art-f17e0bebdccf4243bbe20ce69f73d27f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:15:17Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f17e0bebdccf4243bbe20ce69f73d27f2023-11-29T04:24:15ZengElsevierCell Reports2211-12472023-12-014212113506SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cellsConor M. Henry0Carlos A. Castellanos1Michael D. Buck2Evangelos Giampazolias3Bruno Frederico4Ana Cardoso5Neil C. Rogers6Oliver Schulz7Sonia Lee8Johnathan Canton9Peter Faull10Ambrosius P. Snijders11Bhopal Mohapatra12Hamid Band13Caetano Reis e Sousa14Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKProtein Analysis and Proteomics Labaratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKProtein Analysis and Proteomics Labaratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UKDepartment of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USAEppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USAImmunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Corresponding authorSummary: Cross-presentation of dead cell-associated antigens by conventional dendritic cells type 1 (cDC1s) is critical for CD8+ T cells response against many tumors and viral infections. It is facilitated by DNGR-1 (CLEC9A), an SYK-coupled cDC1 receptor that detects dead cell debris. Here, we report that DNGR-1 engagement leads to rapid activation of CBL and CBL-B E3 ligases to cause K63-linked ubiquitination of SYK and terminate signaling. Genetic deletion of CBL E3 ligases or charge-conserved mutation of target lysines within SYK abolishes SYK ubiquitination and results in enhanced DNGR-1-dependent antigen cross-presentation. We also find that cDC1 deficient in CBL E3 ligases are more efficient at cross-priming CD8+ T cells to dead cell-associated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiquitination in limiting cross-presentation of dead cell-associated antigens and highlight an axis of negative regulation of cDC1 activity that could be exploited to increase anti-tumor immunity.http://www.sciencedirect.com/science/article/pii/S2211124723015188CP: Immunology |
| spellingShingle | Conor M. Henry Carlos A. Castellanos Michael D. Buck Evangelos Giampazolias Bruno Frederico Ana Cardoso Neil C. Rogers Oliver Schulz Sonia Lee Johnathan Canton Peter Faull Ambrosius P. Snijders Bhopal Mohapatra Hamid Band Caetano Reis e Sousa SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells Cell Reports CP: Immunology |
| title | SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells |
| title_full | SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells |
| title_fullStr | SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells |
| title_full_unstemmed | SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells |
| title_short | SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells |
| title_sort | syk ubiquitination by cbl e3 ligases restrains cross presentation of dead cell associated antigens by type 1 dendritic cells |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723015188 |
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