炎症性卡斯帕斯是细胞内LPS的先天免疫受体
Jianjin Shi1, Yue Zhao2, Yupeng Wang3
11] Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, Beijing 102206, China [2] National Institute of Biological Sciences, Beijing 102206, China [3].
Nature
|August 15, 2014
概括
人类的caspase-4和caspase-5,以及小鼠的caspase-11,直接与脂多糖 (LPS) 结合,触发细胞死亡途径. 这一发现揭示了免疫模式识别和酶激活的新机制.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
背景情况:
- 非正规的炎症酶,涉及小鼠caspase-11,对细菌感染作出反应.
- 卡斯帕酶-11的激活会通过细胞质脂聚糖体 (LPS) 传感导致热和内毒性休克,但受体仍然未知.
研究的目的:
- 阐明细胞质LPS感应的机制,并确定负责LPS诱导细胞死亡的模式识别受体.
主要方法:
- 在细胞质递送时研究了LPS诱导的人体细胞 (单细胞,上皮细胞,角质细胞) 的细胞毒性.
- 利用了人类卡斯帕-4和小鼠卡斯帕-11之间的功能补充测试.
- 对卡斯帕酶 (卡斯帕酶-4/11,卡斯帕酶-5) 进行了直接结合试验,对LPS和脂质A进行了直接结合试验.
- 通过使用纯化的昆虫细胞caspases,对LPS结合的caspase寡合化和激活进行了检查.
- 在LPS电穿孔和细菌感染模型中生成并测试具有结合缺陷的CARD域点突变体.
主要成果:
- 人类细胞在细胞质LPS递送时经历死亡,由人体卡斯帕-4介导,这在功能上补充了小鼠卡斯帕-11.
- 人类的caspase-4/11和caspase-5直接结合LPS和脂质A,具有很高的亲和力.
- 结合LPS会诱导酶-4/11的寡合化和激活,这是一个依赖于CARD域的过程.
- 低化LPS变体未能诱导酶激活,这表明特异性.
- 卡特域突变者失去了寡聚化,激活和诱导热的能力.
结论:
- 人类的caspase-4/11和caspase-5作为直接的LPS传感器,调解热和亡.
- 这代表了免疫系统中一种新的模式识别机制,也是酶激活的新途径.
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