CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD.
CD97 stabilises the immunological synapse between dendritic cells and T cells and is targeted for degradation by the Salmonella effector SteD.
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DOI：
10.1371/journal.ppat.1009771
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发表时间：
2021-07
期刊：
影响因子：
6.7
通讯作者：
Holden DW
中科院分区：
文献类型：
--
作者：
Cerny O;Godlee C;Tocci R;Cross NE;Shi H;Williamson JC;Alix E;Lehner PJ;Holden DW
肠道沙门氏菌效应子SteD通过泛素化mMHCII β链的胞质尾，从感染的抗原呈递细胞表面消耗成熟的MHCII类（mMHCII）分子。这需要Nedd 4家族HECT E3泛素连接酶Wwp 2和肿瘤抑制跨膜蛋白衔接子Tmem 127。在这里，通过树突状细胞的蛋白质组学筛选，我们发现SteD通过类似的机制靶向质膜蛋白CD 97进行降解。SteD增强了K555上CD 97的泛素化，并且该残基的突变消除了SteD对CD 97表面水平的影响。我们发现，CD 97定位于树突状细胞和T细胞之间的免疫突触并使其稳定。通过SteD去除CD 97抑制树突状细胞-T细胞相互作用并降低T细胞活化，与其对MHCII的影响无关。因此，SteD通过两个不同的过程抑制T细胞免疫。肠道沙门氏菌是全世界人类和牲畜中非常大量的严重和威胁生命的疾病的病原体。清除S。肠毒素依赖于T细胞介导的免疫应答。我们在这里表明，沙门氏菌SPI-2 III型分泌系统效应物SteD通过减少感染的抗原呈递细胞和T细胞之间的接触来抑制T细胞的活化。这是由粘附G蛋白偶联受体CD 97的降解介导的。我们的工作表明，CD 97稳定了抗原呈递细胞和T细胞之间的相互作用，并将此过程确定为细菌病原体的直接靶标。
The Salmonella enterica effector SteD depletes mature MHC class II (mMHCII) molecules from the surface of infected antigen-presenting cells through ubiquitination of the cytoplasmic tail of the mMHCII β chain. This requires the Nedd4 family HECT E3 ubiquitin ligase Wwp2 and a tumor-suppressing transmembrane protein adaptor Tmem127. Here, through a proteomic screen of dendritic cells, we found that SteD targets the plasma membrane protein CD97 for degradation by a similar mechanism. SteD enhanced ubiquitination of CD97 on K555 and mutation of this residue eliminated the effect of SteD on CD97 surface levels. We showed that CD97 localises to and stabilises the immunological synapse between dendritic cells and T cells. Removal of CD97 by SteD inhibited dendritic cell-T cell interactions and reduced T cell activation, independently of its effect on MHCII. Therefore, SteD suppresses T cell immunity by two distinct processes. Salmonella enterica is the causative agent of very large numbers of serious and life-threatening diseases in humans and livestock throughout the world. Clearance of S. enterica from the host is dependent on T cell-mediated immune responses. We show here that the Salmonella SPI-2 type III secretion system effector SteD inhibits activation of T cells by reducing contacts between infected antigen-presenting cells and T cells. This is mediated by degradation of an adhesion G protein-coupled receptor CD97. Our work reveals that CD97 stabilizes the interaction between antigen-presenting cells and T cells and identifies this process as a direct target for bacterial pathogens.