SARS-CoV-2 Nsp14结合Tollip并激活促炎途径,同时降低干扰素α和干扰素γ受体的调节
Naveen Thakur1, Poushali Chakraborty1, JoAnn M Tufariello1
1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
mBio
|June 25, 2025
概括
严重急性呼吸道综合征冠状病毒2 (SARS-CoV-2) 非结构性蛋白14 (Nsp14) 激活炎症途径并降低干扰素受体的调节. Nsp14-Tollip相互作用调节这些免疫逃避功能.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- SARS-CoV-2 Nsp14具有外核酶 (ExoN) 和甲基转移酶 (N7-MTase) 域.
- 通过激活NF-κB和降低IFNAR1.1的调节,NSP14调节宿主免疫力.
- 目前尚不完全了解NSP14免疫调节的全部程度.
研究的目的:
- 调查SARS-CoV-2 Nsp14对宿主天生的免疫信号通路的更广泛影响.
- 阐明NSP14的域在免疫调节中的作用.
- 确定与NSP14相互作用的宿主因素及其在免疫逃避中的作用.
主要方法:
- 对具有改变ExoN或N7-MTase功能的Nsp14突变的分析.
- 评估NSP14对MAPK信号 (ERK,p38,JNK) 和细胞因子产生的影响.
- 通过溶酶体通路对Nsp14对IFNAR1和IFNGR1表达的影响的研究.
- 同免疫沉用于识别Nsp14相互作用蛋白,包括Tollip.
- 托利普的淘汰和过度表达实验,以评估其在Nsp14介导的免疫调节中的作用.
主要成果:
- Nsp14激活NF-κB,MAPK信号传递 (ERK,p38,JNK) 和细胞因子的产生.
- Nsp14通过感染细胞中的 lysosomal 途径降低 IFNAR1 和 IFNGR1 的调节.
- N7-MTase突变,但不是ExoN突变,会损害NSP14的免疫调节活动.
- 对于N7-MTase活性来说,ExoN域是必需的,这表明了一个功能链接.
- 托利普通过其C2域和C端序列与NSP14相互作用.
- 托利普可以抵消Nsp14介导的NF-κB激活,并且其敲击可以逆转IFNAR1/IFNGR1下调.
结论:
- SARS-CoV-2 Nsp14 具有比以前更广泛的先天免疫调节功能,包括MAPK激活和IFNGR1下调.
- Nsp14的exoN和N7-MTase域都对其免疫逃避活动至关重要.
- 主体蛋白Tollip作为NSP14免疫调节功能的负调节剂,突出了SARS-CoV-2免疫逃避中的新型NSP14-Tollip相互作用.
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