在溶解细胞死亡过程中,NINJ1调解了血破裂
Nobuhiko Kayagaki1, Opher S Kornfeld2, Bettina L Lee2
1Department of Physiological Chemistry, Genentech Inc., South San Francisco, CA, USA. kayagaki@gene.com.
Nature
|January 20, 2021
概括
NINJ1蛋白对血破裂 (PMR) 至关重要,这是临床细胞死亡的关键事件. 这一发现揭示了NINJ1
科学领域:
- 细胞生物学
- 免疫学
- 遗传学
背景情况:
- 血破裂 (PMR) 是临床细胞死亡的终端事件,释放与损伤相关的分子模式 (DAMP),驱动炎症.
- 控制PMR的分子机制在很大程度上是未知的.
- 之前已经确定了NINJ1蛋白,这是一种具有两个跨膜区域的细胞表面蛋白,但其在细胞死亡中的作用尚不清楚.
研究的目的:
- 阐明溶解细胞死亡过程中等离子体膜破裂 (PMR) 的潜在机制.
- 确定PMR过程中的关键分子参与者.
- 研究NINJ1蛋白在PMR中的作用及其对宿主防御的贡献.
主要方法:
- 在随机变异的小鼠中进行前置基因查,以确定调节PMR的基因.
- 分析Ninj1淘汰 (Ninj1-/-) 大细胞和小鼠.
- 通过测量HMGB1和LDH等细胞内蛋白质的释放来评估PMR.
- 显微镜观察细胞死亡过程中的细胞形态.
- 使用Citrobacter rodentium进行感染研究,以评估Ninj1-/-小鼠的宿主防御.
主要成果:
- NINJ1蛋白被确定为PMR的一个重要媒介.
- 在各种细胞死亡途径 (烧死,亡,亡) 中,ninj1-/-巨细胞显示出受损的PMR.
- 忍者1-/-巨细胞表现出有缺陷的细胞解体与持久的气球形态.
- Ninj1-/-小鼠对Citrobacter rodentium感染的敏感性增加,这表明PMR在抗菌防御中的作用.
- 通过其细胞外域的寡合化来诱导NINJ1的功能.
结论:
- NINJ1是血破裂 (PMR) 的关键和进化保存媒介.
- 发现NINJ1的作用挑战了长期以来的PMR作为被动细胞事件的观点.
- NINJ1介导的PMR在抗菌宿主防御中起着重要作用.
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