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NAD的ADP-核糖部分被转移到靶蛋白上，是由细菌毒素和哺乳动物酶家族催化的。一些毒素转移酶似乎是由细菌引起的疾病的原因。哺乳动物酶既位于细胞内和细胞表面，有时是通过糖基磷脂酰肌醇锚固链接的。其他要分泌的哺乳动物转移酶Apppear。哺乳动物酶的家族已被克隆到实验室中。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。NAD-代谢酶（例如ADP-核糖基转移酶（ART）1）在免疫细胞表面的存在表明潜在的免疫调节活性是ECTO NAD或NAD或NAD或NAD或它的代谢产物在炎症部位和细胞裂解部位的NAD水平可能很高。在人类气道中，腔内的上皮细胞和腔内细胞（例如，多形核细胞）参与先天免疫反应并分泌或在其表面NAD上：精氨酸ADP-核糖基转移酶。防御素，由免疫细胞分泌的抗菌肽富含精氨酸，导致假设ADP-核糖基化可以改变其生物学活性。该小组发现ART-1修饰了α-防御素1的精氨酸14。 ADP-核糖基化防御素-1降低了细胞毒性和抗菌活性，但仍刺激了A549细胞的T细胞趋化性和IL-8释放。此外，ADP-核糖基化防御素抑制了未修饰的防御素-1的细胞毒性和抗菌活性。在吸烟者的支气管肺泡灌洗液中鉴定出ADP-核糖基化的防御素-1，但不能来自非吸烟者，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以及其他阳离子分子，在先天免疫反应中具有重要的调节作用，并改变其生物学特性。这些数据表明ADP-核糖基化可能参与调节先天免疫反应。