病原体阻断宿主死亡受体的信号传递,由氨酸GlcNAcylation死亡域的cylation
1College of Biological Sciences, China Agricultural University, Beijing 100094, China.
Nature
|August 20, 2013
概括
肠病原性大肠杆菌使用NleB通过修改死亡领域来抑制宿主免疫反应,阻断关键细胞信号通路,如NF-κB,亡和亡. 这种细菌机制涉及N-乙糖胺转移酶活性,对感染至关重要.
科学领域:
- 微生物学 微生物学
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 瘤坏死因子 (TNF) 信号传递对免疫平衡,炎症和细胞死亡至关重要.
- TNF受体 (TNFR) 家族成员,如TNFR1和FAS,通过死亡域调解这些信号.
- 这些域与适应蛋白 (如TRADD和FADD) 相互作用,触发下游信号.
研究的目的:
- 确定肠病原性大肠杆菌 (EPEC) 抑制宿主免疫信号传递的机制.
- 调查EPEC类型III分泌系统效应器NleB在调节死亡受体通路中的作用.
- 描述NleB的酶活性及其对宿主细胞死亡和炎症的影响.
主要方法:
- 生物化学测试以确定NleB的酶活性.
- 位点定向突变发生,以确定NleB中的关键残留物,并准死亡领域.
- 基于细胞的测试来评估NF-κB信号传递,亡和亡.
- 在体内感染模型来评估NleB在细菌殖民中的作用.
主要成果:
- NleB具有N-乙葡萄糖胺 (GlcNAc) 转移酶活性,在包括TRADD,FADD,RIPK1和TNFR1.1在内的蛋白质的死亡域中修改保存的氨酸.
- 这种GlcNAcylation使死亡域失活,阻止了必不可少的蛋白质-蛋白质相互作用和TNFR1复合体和DISC等信号复合体的组装.
- 在EPEC感染的细胞中观察到TNF,NF-κB,亡和亡信号的破坏.
- 在小鼠模型中,NleB的GlcNAc转移酶活性对于EPEC殖民是必不可少的.
结论:
- 来自EPEC的NleB通过死亡域的新型后翻译修饰 (GlcNAcylation) 直接抑制宿主TNFR和FAS信号通路.
- 这种细菌策略有效地抵消宿主免疫反应,包括炎症和细胞死亡.
- 发现NleB的氨酸GlcNAc转移酶活性揭示了细菌致病的新机制和一种未被认可的蛋白质修饰形式.
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