病毒和甲基动物毒素是限制cGAS-STING信号的cGAMP特定核酶
James B Eaglesham1,2,3, Youdong Pan4, Thomas S Kupper4,5
1Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
Nature
|February 8, 2019
概括
病毒免疫核酶 (毒素) 降解2
科学领域:
- 免疫学
- 病毒学
- 结构生物学
背景情况:
- 细胞核DNA通过循环GMP-AMP合成酶 (cGAS) 和2',3'-循环GMP-AMP (cGAMP) 激活先天免疫.
- STING通路对于免疫信号传递至关重要,但缺乏已知的2',3'-cGAMP内源抑制剂.
- 病毒已经进化了逃避宿主天生的免疫反应的机制.
研究的目的:
- 为了确定降解2',3'-cGAMP的宿主或病毒因素.
- 描述新型2',3'-cGAMP降解酶的功能和机制.
- 研究这些酶在病毒病变和先天免疫逃避中的作用.
主要方法:
- 对24种哺乳动物病毒进行生物化学查.
- 对2',3'-cGAMP降解的酶活性测定.
- 疫苗病毒毒素的晶体结构的确定.
- 在疫苗病毒中进行基因删除研究.
- 对昆虫和细菌病毒中毒素同类物的生物信息分析.
主要成果:
- 鉴定出毒虫病毒免疫核酶 (毒素) 是一种降解2',3'- cGAMP的酶.
- 毒素分裂2',3'-cGAMP,限制了依赖STING的信号传递.
- 删除疫苗病毒毒素基因 (B2R) 在体内减少病毒复制.
- 晶体结构显示了选择性2',3'-cGAMP水解的金属独立机制.
- 在昆虫的毒毒病毒及其宿主中发现了保存的毒毒同类物,这表明它们的作用很古老.
结论:
- 毒素代表了一种新的2',3'-cGAMP特异性核酶家族.
- 病毒利用毒素降解2',3'-cGAMP并逃避cGAS-STING介导的先天免疫力.
- 毒素在天花病毒的发病过程中起着重要作用,并且具有与cGAS-STING调节有关的古老的进化历史.
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