Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Nat Commun. 2018 Apr 19;9(1):1560. doi: 10.1038/s41467-018-03669-z.
The NLRP3 inflammasome has an important function in inflammation by promoting the processing of pro-IL-1β and pro-IL-18 to their mature bioactive forms, and by inducing cell death via pyroptosis. Here we show a critical function of the E3 ubiquitin ligase Pellino2 in facilitating activation of the NLRP3 inflammasome. Pellino2-deficient mice and myeloid cells have impaired activation of NLRP3 in response to toll-like receptor priming, NLRP3 stimuli and bacterial challenge. These functions of Pellino2 in the NLRP3 pathway are dependent on Pellino2 FHA and RING-like domains, with Pellino2 promoting the ubiquitination of NLRP3 during the priming phase of activation. We also identify a negative function of IRAK1 in the NLRP3 inflammasome, and describe a counter-regulatory relationship between IRAK1 and Pellino2. Our findings reveal a Pellino2-mediated regulatory signaling system that controls activation of the NLRP3 inflammasome.
NLRP3 炎性小体通过促进 pro-IL-1β 和 pro-IL-18 加工为成熟的生物活性形式，并通过细胞焦亡诱导细胞死亡，在炎症中具有重要功能。在这里，我们展示了 E3 泛素连接酶 Pellino2 在促进 NLRP3 炎性小体激活中的关键作用。Pellino2 缺陷小鼠和髓样细胞在 TLR 引发、NLRP3 刺激和细菌挑战下，NLRP3 的激活受损。Pellino2 在 NLRP3 通路中的这些功能依赖于 Pellino2 FHA 和 RING 样结构域，Pellino2 在激活的引发阶段促进 NLRP3 的泛素化。我们还确定了 IRAK1 在 NLRP3 炎性小体中的负调控作用，并描述了 IRAK1 和 Pellino2 之间的反向调控关系。我们的研究结果揭示了一个 Pellino2 介导的调节信号系统，该系统控制 NLRP3 炎性小体的激活。
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