气体皮质D孔结构显示成熟的互白素-1的优先释放
Shiyu Xia1,2, Zhibin Zhang1,3, Venkat Giri Magupalli1,2
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
Nature
|April 22, 2021
概括
形成细胞因子释放和细胞死亡的毛孔. 这些毛孔使用静电过来选择性地释放成熟的IL-1β和IL-18,显示电荷
科学领域:
- 天生的免疫力
- 分子和细胞生物学
- 结构生物学
背景情况:
- 炎症酶激活卡斯帕斯,分裂气皮D (GSDMD).
- GSDMD形成毛孔,释放IL-1细胞因子并驱动热.
- 卡斯巴酶1将IL-1家族的前体转化为成熟的细胞因子.
研究的目的:
- 确定GSDMD孔隙和预孔状态的冷电子显微镜结构.
- 研究由GSDMD介导的IL-1细胞因子释放的机制.
- 阐明GSDMD孔充电在货物的选择性中的作用.
主要方法:
- 用冷电子显微镜 (cryo-EM) 来解析 GSDMD 的结构.
- 脂质细胞透测试以评估货物释放.
- 研究IL-1β分泌的巨细胞实验.
- GSDMD酸性残留物的位点定向突变.
主要成果:
- GSDMD结构显示出具有膜结合元件的明显孔隙和预孔隙构造.
- GSDMD孔管主要是负电荷.
- GSDMD毛孔表现出静电过,有利于释放带正电荷/中性分子和成熟的IL-1β/IL-18,而不是前体.
- 突变的GSDMD酸性残留物会影响IL-1β的选择性释放.
结论:
- GSDMD孔隙形成对于炎症酶介导的IL-1释放至关重要.
- 通过负电荷的GSDMD孔介导的静电相互作用控制了选择性细胞因子的运输.
- GSDMD作为一个大小和电荷选择性通道,影响先天免疫反应.
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