ADP-ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS toxin regulates inflammasome activity.
ADP-ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS toxin regulates inflammasome activity.
复制标题
DOI：
10.1128/mbio.02186-14
复制
发表时间：
2014-12-23
期刊：
影响因子：
6.4
通讯作者：
Baseman JB
中科院分区：
文献类型：
--
作者：
Bose S;Segovia JA;Somarajan SR;Chang TH;Kannan TR;Baseman JB
炎症小体是炎症的主要调节因子，它通过激活原天冬氨酸酶-1，将前白介素1β(原-白介素1β)裂解成成熟的形式。IL-1β是一种关键的促炎细胞因子，它决定了与多种炎症性疾病相关的炎症的严重程度。NLRP3是炎症体复合体的关键成分，多种信号和刺激触发了NLRP3炎症体复合体的形成。在目前的研究中，我们发现了一种尚不清楚的NLRP3炎性小体被病原体衍生因子激活的机制。我们发现由肺炎支原体产生的独特的细菌ADP-核糖化和空泡化毒素和指定的社区获得性呼吸窘迫综合征(CADS)毒素通过与NLRP3炎症体共定位并催化NLRP3的ADP-核糖化来激活NLRP3炎症体。缺乏ADP-核糖基转移酶(ADPRT)活性的突变型全长CADS毒素和不能与巨噬细胞结合并内化的截短CADS毒素不能激活NLRP3炎症体。这些研究表明，CARDS毒素介导的腺苷二磷酸核糖化是NLRP3重要的翻译后修饰，CARDS毒素的ADPRT活性是NLRP3炎症体激活所必需的，翻译后ADPRT介导的炎症体修饰是一种新发现的炎症体激活机制，继而释放IL-1β和相关的病理机制。炎症是对包括感染在内的环境因素的一种基本的先天免疫反应。炎症体代表一种多蛋白复合体，通过激活特定的促炎细胞因子来调节炎症，从而产生有效的宿主保护性反应。然而，感染后可能会过度释放促炎细胞因子，从而扭曲宿主对“过度炎症”的反应，造成夸大的组织损伤。肺炎支原体是一种常见的呼吸道细菌病原体，具有一种独特的蛋白毒素，具有ADP核糖基转移酶和空泡化特性，能够复制与支原体感染相关的强烈炎症和细胞病理学。在这里，我们证明了这种毒素通过与NLRP3共定位和ADP-核糖基化NLRP3来独特地激活NLRP3炎症小体，可能导致“过度炎症”，从而发现了治疗干预的新靶点。
The inflammasome is a major regulator of inflammation through its activation of procaspase-1, which cleaves prointerleukin-1β (pro-IL-1β) into its mature form. IL-1β is a critical proinflammatory cytokine that dictates the severity of inflammation associated with a wide spectrum of inflammatory diseases. NLRP3 is a key component of the inflammasome complex, and multiple signals and stimuli trigger formation of the NLRP3 inflammasome complex. In the current study, we uncovered a yet unknown mechanism of NLRP3 inflammasome activation by a pathogen-derived factor. We show that the unique bacterial ADP-ribosylating and vacuolating toxin produced by Mycoplasma pneumoniae and designated community-acquired respiratory distress syndrome (CARDS) toxin activates the NLRP3 inflammasome by colocalizing with the NLRP3 inflammasome and catalyzing the ADP-ribosylation of NLRP3. Mutant full-length CARDS toxin lacking ADP-ribosyltransferase (ADPRT) activity and truncated CARDS toxins unable to bind to macrophages and be internalized failed to activate the NLRP3 inflammasome. These studies demonstrate that CARDS toxin-mediated ADP-ribosylation constitutes an important posttranslational modification of NLRP3, that ADPRT activity of CARDS toxin is essential for NLRP3 inflammasome activation, and that posttranslational ADPRT-mediated modification of the inflammasome is a newly discovered mechanism for inflammasome activation with subsequent release of IL-1β and associated pathologies. Inflammation is a fundamental innate immune response to environmental factors, including infections. The inflammasome represents a multiprotein complex that regulates inflammation via its ability to activate specific proinflammatory cytokines, resulting in an effective host protective response. However, excessive release of proinflammatory cytokines can occur following infection that skews the host response to “hyperinflammation” with exaggerated tissue damage. Mycoplasma pneumoniae, a common bacterial airway pathogen, possesses a unique protein toxin with ADP-ribosyltransferase and vacuolating properties capable of reproducing the robust inflammation and cytopathology associated with mycoplasma infection. Here, we show that the toxin uniquely activates the NLRP3 inflammasome by colocalizing with and ADP-ribosylating NLRP3, possibly leading to “hyperinflammation” and thus uncovering a novel target for therapeutic intervention.