通过使LUBAC脱,OTULIN可以抑制细胞死亡和炎症
Klaus Heger1, Katherine E Wickliffe1, Ada Ndoja1
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|June 29, 2018
概括
这种复合物对预防炎症和胚胎致死性至关重要. OTULIN功能丧失导致细胞死亡和I型干扰素的产生.
科学领域:
- 细胞生物学
- 免疫学
- 分子生物学
背景情况:
- OTULIN (具有线性链接特异性的OTU二基因酶) 从LUBAC (线性泛链组合复合体) 基板中去除线性多基因.
- OTULIN对于预防自身炎症疾病和胚胎致死性至关重要.
研究的目的:
- 研究OTULIN在调节LUBAC活动中的确切作用及其下游后果.
- 阐明OTULIN缺乏导致胚胎死亡和自身炎症的机制.
主要方法:
- 产生具有催化不活性OTULIN的模拟小鼠.
- 在OTULIN缺陷模型中分析细胞死亡途径 (TNFR1, RIPK1, caspase 8, RIPK3).
- 在突变小鼠中评估I型干扰素的产生.
主要成果:
- 由于TNFR1/ RIPK1介导的细胞死亡,导致妊娠中期的胚胎死亡.
- 在成年小鼠中,OTULIN的无活化会触发促炎细胞死亡,而这种细胞死亡会通过酶8和RIPK3的联合丧失而恢复.
- 缺少卡斯巴酶8和RIPK3的OTULIN突变小鼠表现为具有增强RIPK1依赖的I型干扰素产生的围产死亡率.
结论:
- OTULIN和LUBAC的功能是线性的,OTULIN通过防止LUBAC的自主无处不在来促进它的活性.
- 在调节细胞死亡途径和I型干扰素诱导方面,OTULIN起着至关重要的作用.
- 这些发现揭示了线性无处不在,细胞死亡和先天免疫反应之间的新联系.
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