Molecular and functional analyses of CD25 as a target for ADP-ribosylation on CD4+/CD25+ regulatory T cells

NAD依赖的ADP核糖基化是一种翻译后蛋白质修饰，是细菌毒素的致病机制。ART 2是一种毒素相关的精氨酸特异性ADP-核糖基转移酶，由鼠T细胞表达为与脂筏相关的胞外酶。炎症导致ART 2底物NAD从受损细胞中释放。ART 2然后催化筏相关信号蛋白的ADP-核糖基化。ART 2在T细胞活化时作为活性酶从T细胞表面脱落。脱落ART 2 ADP-核糖基化分泌蛋白，包括某些细胞因子。膜蛋白和分泌蛋白的ADP核糖裂解可以深刻地影响炎症细胞的功能、细胞间通讯和相互作用。我们最近发现，CD 25，白细胞介素-2受体的α链，由调节性T细胞组成性表达，是ADP-核糖基化的突出靶点。该项目的目标是鉴定CD 25中作为ADP-核糖基化受体的精氨酸残基，并确定这种修饰对CD 25功能的影响。此外，我们将评估CD 25-ADP-核糖基化对调节性T细胞功能的影响。

NAD-dependent ADP-ribosylation is one of the posttranslational protein modifications, best known as the pathogenic mechanism of bacterial toxins. ART2 is a toxin-related argininespecific ADP-ribosyltransferase that is expressed by murine T cells as an ecto-enzyme in association with lipid rafts. Inflammation leads to the release of the ART2 substrate NAD from damaged cells. ART2 then catalyzes ADP-ribosylation of raft-associated signalling proteins. ART2 is shed from the T cell surface as an active enzyme upon T cell activation. Shed ART2 ADP-ribosylates secretory proteins including certain cytokines. ADP-riboslyation of membrane and secretory proteins can profoundly influence the function, intercellular communication, and interaction of inflammatory cells. We recently discovered that CD25, the alpha chain of the interleukin-2 receptor, which is constirutively expressed by regulatroy T cells, is a prominent target for ADP-ribosylation. The goal of the proposed project is to identify the arginine residue in CD25 that serves as the acceptor for ADP-ribosylation and to determine the consequences of this modification for the function of CD25. Moreover we will evaluate the effects of CD25-ADP-ribosylation on the function of regulatory T cells.