通过全身老鼠NLRP3结构控制通路的激活显示NLRP3
Liudmila Andreeva1, Liron David1, Shaun Rawson2
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Cell
|December 3, 2021
概括
含有NACHT,丰富的重复蛋白 (LRR) 和pyrin域的蛋白3 (NLRP3) 在细胞膜上形成双环. 这种结构对于感知细胞损伤和启动炎酶激活至关重要,为慢性炎症治疗提供了新的点.
科学领域:
- 细胞生物学
- 免疫学
- 结构生物学
背景情况:
- 含有NACHT,丰富的重复蛋白 (LRR) 和pyrin域的蛋白3 (NLRP3) 炎症体是细胞损伤的关键传感器,也是慢性炎症疾病的治疗点.
- 目前尚不完全了解NLRP3在膜上的精确结构和激活机制.
研究的目的:
- 阐明全身老鼠NLRP3的内源性刺激反应结构.
- 研究NLRP3的寡合结构在炎症酶激活和细胞反应中的作用.
主要方法:
- 用冷电子显微镜测定NLRP3寡合物的结构.
- 通过结构引导的突变发生来检测特定的NLRP3域和相互作用的功能.
- 基于细胞的测试以评估炎症酶激活,酶-1处理和细胞死亡.
主要成果:
- 鉴定了一种全长老鼠NLRP3的12至16-mer双环结构,主要局限于膜.
- 证明LRR-LRR相互作用稳定了双环,屏蔽了pyrin域并防止过早激活.
- 表明双环结构的破坏会损害跨戈尔吉网络的分散,炎性点体的形成,酶-1处理和细胞死亡.
结论:
- 在生理上,NLRP3是准备激活的与膜相关的双环寡合体.
- 这种寡合结构对于感知各种细胞应激信号和启动炎症体路径至关重要.
- 这些发现为NLRP3炎症酶调节提供了关键的洞察力,并提出了炎症状况的新治疗策略.
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