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

被引：3

作者：

Henry, Conor M. ^{[1
,5
]}

Castellanos, Carlos A. ^{[1
]}

Buck, Michael D. ^{[1
]}

Giampazolias, Evangelos ^{[1
,6
]}

Frederico, Bruno ^{[1
]}

Cardoso, Ana ^{[1
]}

Rogers, Neil C. ^{[1
]}

Schulz, Oliver ^{[1
]}

Lee, Sonia ^{[1
]}

Canton, Johnathan ^{[1
,7
]}

Faull, Peter ^{[2
,5
]}

Snijders, Ambrosius P. ^{[2
,8
,9
]}

Mohapatra, Bhopal ^{[3
]}

Band, Hamid ^{[4
]}

Sousa, Caetano Reis e ^{[1
]}

机构：

[1] Francis Crick Inst, Immunobiol Lab, 1 Midland Rd, London NW1 1AT, England

[2] Francis Crick Inst, Prot Anal & Prote Platform, 1 Midland Rd, London NW1 1AT, England

[3] Univ Nebraska Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE USA

[4] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE USA

[5] Roche Prod Ltd, Welwyn Garden City AL7 1TW, Herts, England

[6] Univ Manchester, Canc Res UK Manchester Inst, Canc Immunosurveillance Grp, Alderley Pk, Manchester M13 9PL, England

[7] Univ Calgary, Fac Vet Med, Comparat Biol & Expt Med, Calgary, AB, Canada

[8] Northwestern Univ, Northwestern Prote Core Facil, Chicago, IL 60611 USA

[9] Life Sci Mass Spectrometry, Bruker Dalton, Banner Lane, Coventry CV4 9GH, England

来源：

CELL REPORTS | 2023年 / 42卷 / 12期

基金：

英国惠康基金; 英国医学研究理事会; 欧盟地平线“2020”;

关键词：

C-CBL; TYROSINE KINASE; F-ACTIN; DYING CELLS; T-CELLS; RECEPTOR; ACTIVATION; DNGR-1; CD8(+); INFECTION;

D O I：

10.1016/j.celrep.2023.113506

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 abol-ishes 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 -asso-ciated antigens and promoting host resistance to tumors. Our findings reveal a role for CBL-dependent ubiq-uitination 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.

引用

页数：24