通过非正规性炎症酶-4识别和成熟IL-18
Xuyan Shi1, Qichao Sun2,3, Yanjie Hou2
1National Institute of Biological Sciences, Beijing, Beijing, P. R. China.
Nature
|November 22, 2023
概括
人类卡斯帕-4,与小鼠卡斯帕-11不同,处理关键细胞因子IL-18. 这一发现阐明了非正规的炎症酶功能和IL-18的作用.
科学领域:
- 免疫学
- 分子生物学
- 结构生物学
背景情况:
- 规范性 (caspase-1) 和非规范性 (caspase-4/5/11) 炎症细胞分裂气体皮质D (GSDMD) 以诱导热.
- 卡斯巴酶1对IL-1β和IL-18进行处理,但脂糖激活的卡斯巴酶4/5/11的点在很大程度上是未知的.
- 对于免疫和疾病研究来说,了解非正规的炎症体目标至关重要.
研究的目的:
- 确定脂聚糖激活的卡斯帕-4/5/11是否可以处理IL-18.
- 阐明-4/5/11与亲IL-18相互作用的分子机制.
- 调查 IL-18 处理中的特定物种差异的结构基础.
主要方法:
- 在实验室中使用复合人-4和小鼠-11.
- 测定-4-pro-IL-18复合物的晶体结构.
- 在体内评估IL-18的细菌感染模型.
主要成果:
- 人类的caspase-4,但不是小鼠的caspase-11,在试验室和细菌感染期间有效地处理pro-IL-18.
- 晶体结构显示了一种双基质识别机制,涉及亲IL-18的催化和外位相互作用.
- 卡斯帕-4,-5和-1使用类似的二进制识别对亲IL-18,而卡斯帕-11的异位偏差阻止结合.
- 通过酶-1,-4或-5的裂变诱导IL-18的结构变化,产生受体结合位.
结论:
- 鉴定出IL-18是脂聚糖激活的人类卡斯帕-4/5的直接标.
- 这项研究揭示了理解非正规性炎症酶介导防御机制的范式转变.
- 这些发现增强了对IL-18在免疫和疾病发病中的作用的理解.
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