HERC5催化ISGylation增强了cGAS介导的先天性免疫力
1State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, China.
Cell reports
|February 29, 2024
概括
循环GMP-AMP合成酶 (cGAS) 途径是由ISG15结合调节的. 这一过程增强了cGAS活性,增强了对病毒感染和炎症基因表达的天生的免疫力.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 病毒学 病毒学
背景情况:
- 循环GMP-AMP合成酶 (cGAS) 是细胞质DNA的关键传感器,启动I型干扰素反应,对抗病毒免疫至关重要.
- 严格调节cGAS活动对于有效的先天免疫反应和预防自身免疫性疾病至关重要.
研究的目的:
- 研究ISG15结合在调节cGAS活动中的作用.
- 阐明ISG15结合影响cGAS功能和下游信号的机制.
主要方法:
- 西方涂抹和免疫沉以检测cGAS的ISGylation.
- 位点定向突变发生,以确定关键的氨酸残留物和HERC5相互作用域.
- 酶活性测定测量cGAS催化功能.
- 细胞测试以评估炎症基因表达和抗病毒活性.
- 使用淘汰赛小鼠进行体内研究,以评估单纯疹病毒1感染.
主要成果:
- 在特定的 lysine 残留物 (21, 187, 219, 458) 上,HERC5 E3 酶催化了 cGAS 的 ISG15 结合.
- Ubl碳基终端化酶18从cGAS中解了ISG15.
- HERC5与cGAS的C端域结合,ISGylation增强了cGAS的寡合化和酶活性.
- 缺少ISG15或HERC5会损害cGAS-STING通路的信号传递,减少炎症基因表达,并影响抗病毒防御.
- 缺乏Isg15或Herc6的小鼠对简单疹病毒1感染的敏感性增加.
结论:
- ISG15结合作为一个积极的反机制,以增强cGAS介导的先天免疫力.
- 这种调节循环放大了细胞对细胞核DNA的细胞反应,加强了抗病毒防御.
- 这些发现揭示了cGAS-STING通路中的新调节层,对传染病和自身免疫性疾病有影响.
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