Adp-ribosylation Cycles

Adp-核糖基化循环

• 批准号: 6671691
• 负责人: Joel Moss
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6671691
• 关键词: ADP ribosylation; NAD nucleosidase; adenine phosphoribosyltransferase; bacterial toxins; immunomodulators; laboratory rat; lymphocyte proliferation; nicotinamide adenine dinucleotide; pentosyltransferase; phosphatidylinositols; posttranslational modifications; protein sequence; protein structure function; pyrophosphatase; tissue /cell culture

ADP-ribosylation, in which the ADP-ribose moiety of NAD is transferred to a target protein, is catalyzed by a family of bacterial toxins and mammalian enzymes. Some toxin transferases appear to be responsible for the diseases caused by the bacterium. The mammalian enzymes are located both within the cell and on the cell surface, sometimes, linked through a glycosylphosphatidylinositol anchor. Other mammalian transferases apppear to be secreted. A family of the mammalian enzymes have been cloned in the laboratory. Of note, these enzymes are specifically expressed in cells involved in the inflammatory response.The presence of NAD-metabolizing enzymes (e.g., ADP-ribosyltransferase (ART)1) on the surface of immune cells suggests a potential immunomodulatory activity for ecto-NAD or its metabolites at sites of inflammation and cell lysis where extracellular levels of NAD may be high. In human airways, epithelial cells lining the lumen and intraluminal cells (e.g., polymorphonuclear cells) participate in the innate immune response and secrete or have on their surface NAD:arginine ADP-ribosyltransferases. Defensins, antimicrobial peptides secreted by immune cells, are arginine-rich, leading to the hypothesis that ADP-ribosylation could modify their biological activities. The group found that ART-1 modifies arginine-14 of alpha-defensin-1. ADP-ribosylated defensin-1 had decreased cytotoxic and antimicrobial activities but still stimulated T-cell chemotaxis and IL-8 release from A549 cells. In addition, ADP-ribosylated defensin inhibited the cytotoxic and antimicrobial activities of unmodified defensin-1. ADP-ribosylated defensin-1 was identified in bronchoalveolar lavage fluid from smokers, but not from nonsmokers, confirming its existence in vivo. Thus, airway NAD:arginine ADP-ribosyltransferases could have an important regulatory role in the innate immune response through modification of alpha defensin-1, and perhaps other cationic molecules, with alteration of their biological properties. These data suggest that ADP-ribosylation may be involved in modulating the innate immune response.

ADP-核糖基化，其中NAD的ADP-核糖部分被转移到靶蛋白，由细菌毒素和哺乳动物酶家族催化。一些毒素转移酶似乎是由细菌引起的疾病的原因。哺乳动物酶位于细胞内和细胞表面，有时通过糖基磷脂酰肌醇锚连接。其他哺乳动物转移酶似乎是分泌的。哺乳动物的一个酶家族已在实验室中克隆出来。值得注意的是，这些酶在参与炎症反应的细胞中特异性表达。ADP-核糖基转移酶（ART）1）在免疫细胞表面的表达表明，胞外NAD或其代谢物在炎症和细胞溶解部位具有潜在的免疫调节活性，其中胞外NAD水平可能较高。在人类气道中，内衬管腔的上皮细胞和管腔内细胞（例如，多形细胞）参与先天性免疫应答并分泌或在其表面上具有NAD：精氨酸ADP-核糖基转移酶。防御素是由免疫细胞分泌的抗菌肽，富含精氨酸，这导致了ADP-核糖基化可以改变其生物学活性的假设。研究小组发现ART-1修饰了α-防御素-1的精氨酸-14。ADP-核糖基化防御素-1的细胞毒性和抗菌活性降低，但仍然刺激T细胞的趋化性和IL-8从A549细胞的释放。此外，ADP-核糖基化防御素抑制未经修饰的防御素-1的细胞毒性和抗微生物活性。在吸烟者的支气管肺泡灌洗液中发现了ADP-核糖基化防御素-1，但在非吸烟者中没有发现，证实了其在体内的存在。因此，气道NAD：精氨酸ADP-核糖基转移酶可以通过修饰α防御素-1和其他阳离子分子，改变其生物学特性，在先天免疫应答中发挥重要的调节作用。这些数据表明，ADP-核糖基化可能参与调节先天免疫反应。