统一的聚合机制用于组装ASC依赖的炎症酶体
Alvin Lu1, Venkat Giri Magupalli1, Jianbin Ruan1
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
|March 18, 2014
概括
炎症体通过一个统一的机制组装,其中包括两个聚合步骤. 这一过程由适配器ASC丝驱动,导致caspase-1激活,用于宿主防御.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 炎症细胞是细胞内先天性免疫传感器,对宿主防御至关重要.
- 关键组件包括传感器蛋白 (例如,AIM2,NLRP3) 和ASC适配蛋白,它将传感器连接到caspase-1.
- ASC通过皮林 (PYD) 和酶激活和招募域 (CARD) 调解相互作用.
研究的目的:
- 为了阐明ASC依赖性炎症酶的组装机制.
- 确定ASC发光线形成的结构基础及其在caspase-1激活中的作用.
- 为了调查不同炎症细胞家族是否存在统一的组装机制.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定ASC PYD丝的结构.
- 结构引导的突变发生,以确认PYD/PYD相互作用.
- 生物化学试验用于研究炎症细胞复合体的形成和激活.
主要成果:
- ASC 的 PYD 和 CARD 域都形成了细丝.
- 已激活的AIM2和NLRP3传感器将ASC PYD丝核,然后将ASC CARD集成在一起.
- ASC核化卡斯帕-1 CARD 纤维,促进近距离诱导的卡斯帕-1 激活.
- ASC PYD 线程的冷-EM 结构揭示了 homo-和 hetero-PYD 关联的细节.
结论:
- 依赖ASC的炎症酶共享一个统一的组装机制,涉及连续的核化诱导的聚合.
- 这个机制利用ASC PYD细丝来核化caspase-1 CARD细丝,从而导致激活.
- 这些发现为理解炎症细胞组合和潜在的治疗向提供了一个结构模板.
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