SYK ubiquitination by CBL E3 ligases restrains cross-presentation of dead cell-associated antigens by type 1 dendritic cells

• Published in: Cell reports (Cambridge) 2023-12, Vol.42 (12), p.113506-113506, Article 113506
• Main Authors: Henry, Conor M., Castellanos, Carlos A., Buck, Michael D., Giampazolias, Evangelos, Frederico, Bruno, Cardoso, Ana, Rogers, Neil C., Schulz, Oliver, Lee, Sonia, Canton, Johnathan, Faull, Peter, Snijders, Ambrosius P., Mohapatra, Bhopal, Band, Hamid, Reis e Sousa, Caetano
• Format: Article
• Language: English
• Subjects: anti-tumor immunity; CBL E3 ligase; CD8+ T cells; CP: Immunology; cross-presentation; cross-priming; dendritic cells; DNGR-1/CLEC9A; spleen tyrosine kinase; SYK
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113506

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. [Display omitted] •CBL and CBL-B E3 ligases are recruited to the activated DNGR-1 receptor complex•CBL E3 ligases ubiquitinate SYK to terminate DNGR-1 signaling•Loss of CBL E3 ligases increases phagosomal rupture induced by DNGR-1 signals•This promotes enhanced cross-presentation of dead cell-associated antigens Henry et al. show that signaling by DNGR-1 in cDC1 is under stringent negative feedback regulation by CBL E3 ligases. The latter ubiquitinate the key adaptor SYK to terminate DNGR-1 signaling. cDC1s lacking CBL family E3 ligases are more potent at cross-presentation of dead cell-associated antigens.