The Francis Crick Institute
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SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells.

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journal contribution
posted on 2023-12-04, 12:55 authored by 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
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.


Crick (Grant ID: CC2090, Grant title: Reis e Sousa CC2090) Wellcome Trust (Grant ID: 106973/Z/15/Z, Grant title: WT 106973/Z/15/Z) Wellcome Trust (Grant ID: 223136/Z/21/Z, Grant title: WT 223136/Z/21/Z) Crick (Grant ID: 10011, Grant title: STP Proteomics) European Commission (Grant ID: 792770 - ActinSensor, Grant title: EC 792770 - ActinSensor) European Commission (Grant ID: 837951 - DC Metabolism, Grant title: EC 837951 - DC Metabolism)