Laboratory of B cell development, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
Immunology. 2013 Aug;139(4):428-37. doi: 10.1111/imm.12099.
ADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. There are two major families of enzymes that catalyse this reaction: extracellular ADP-ribosyl-transferases (ARTs), which are bound to the cell membrane by a glycosylphosphatidylinositol anchor or are secreted, and poly(ADP-ribose)-polymerases (PARPs), which are present in the cell nucleus and/or cytoplasm. Recent findings revealed a wide immunological role for ADP-ribosylating enzymes. ARTs, by sensing extracellular NAD concentration, can act as danger detectors. PARP-1, the prototypical representative of the PARP family, known to protect cells from genomic instability, is involved in the development of inflammatory responses and several forms of cell death. PARP-1 also plays a role in adaptive immunity by modulating the ability of dendritic cells to stimulate T cells or by directly affecting the differentiation and functions of T and B cells. Both PARP-1 and PARP-14 (CoaSt6) knockout mice were described to display reduced T helper type 2 cell differentiation and allergic responses. Our recent findings showed that PARP-1 is involved in the differentiation of Foxp3+ regulatory T (Treg) cells, suggesting a role for PARP-1 in tolerance induction. Also ARTs regulate Treg cell homeostasis by promoting Treg cell apoptosis during inflammatory responses. PARP inhibitors ameliorate immune-mediated diseases in several experimental models, including rheumatoid arthritis, colitis, experimental autoimmune encephalomyelitis and allergy. Together these findings show that ADP-ribosylating enzymes, in particular PARP-1, play a pivotal role in the regulation of immune responses and may represent a good target for new therapeutic approaches in immune-mediated diseases.
ADP-核糖基化是将一个或多个（多达数百个）ADP-核糖基部分添加到受体蛋白上。有两种主要的酶家族催化这种反应：细胞外 ADP-核糖基转移酶（ARTs），它们通过糖基磷脂酰肌醇锚定结合在细胞膜上或被分泌，以及多（ADP-核糖）聚合酶（PARPs），它们存在于细胞核和/或细胞质中。最近的发现揭示了 ADP-核糖基化酶的广泛免疫作用。ARTs 通过感知细胞外 NAD 浓度，可以作为危险探测器。PARP-1 是 PARP 家族的典型代表，已知可以保护细胞免受基因组不稳定性的影响，它参与炎症反应和几种形式的细胞死亡的发展。PARP-1 还通过调节树突状细胞刺激 T 细胞的能力或直接影响 T 和 B 细胞的分化和功能，在适应性免疫中发挥作用。PARP-1 和 PARP-14（CoaSt6）敲除小鼠被描述为显示出减少的辅助性 T 细胞 2 型（Th2）细胞分化和过敏反应。我们最近的发现表明，PARP-1 参与了 Foxp3+调节性 T（Treg）细胞的分化，提示 PARP-1 在诱导耐受中发挥作用。ARTs 还通过在炎症反应中促进 Treg 细胞凋亡来调节 Treg 细胞的动态平衡。PARP 抑制剂在几种实验模型中改善了免疫介导的疾病，包括类风湿关节炎、结肠炎、实验性自身免疫性脑脊髓炎和过敏。这些发现表明，ADP-核糖基化酶，特别是 PARP-1，在调节免疫反应中起着关键作用，可能成为免疫介导的疾病新治疗方法的良好靶点。
