艾滋病毒-1侵占混合电荷域依赖的CPSF6相分离,用于更高阶囊结合,核进入和病毒DNA集成
Sooin Jang1,2, Gregory J Bedwell1,2, Satya P Singh3
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Nucleic acids research
|September 11, 2024
概括
CPSF6的C端混合电荷域 (MCD) 对HIV-1集成至关重要. 这种MCD驱动与病毒体的液态凝结,促进核进入和致病.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 艾滋病毒-1集成优先发生在核斑点 (NS) 附近.
- 病毒感染触发了与NS相关的体依赖的CPSF6凝结物.
- CPSF6表现出液-液相分离 (LLPS) 活性,但其域在LLPS和HIV-1感染中的作用尚不清楚.
研究的目的:
- 调查CPSF6内在无序区域,特别是类域 (PrLD) 和C端混合电荷域 (MCD) 对LLPS和HIV-1感染的贡献.
- 阐明MCD依赖凝聚在HIV-1核后事件中的作用.
主要方法:
- 在体外LLPS测定使用纯化的CPSF6域.
- 感染表达野生型和突变CPSF6蛋白质 (MCD删除,FG突变) 的细胞.
- 病毒核透,集成和囊结合亲缘关系的分析.
- 核光斑耗尽实验. 核光斑耗尽实验. 核光斑耗尽实验.
主要成果:
- 在体外,PrLD和MCD都对CPSF6LLPS有所贡献.
- 类似于FG突变的MCD删除导致HIV-1感染在核边缘停止.
- 异质性MCD在CPSF6被删除的细胞中挽救了HIV-1感染,而SR蛋白域则没有.
- 通过MCD调解的LLPS-依赖的高阶结合和与病毒囊体的共同聚合.
- 核斑耗尽减少了CPSF6点数,但没有影响染色体的整合.
- 将MCD附加到异质蛋白质上,部分恢复了敲除细胞中的核透和集成.
结论:
- 在MCD依赖的CPSF6与病毒体的凝结对于HIV-1感染的核后进入步骤至关重要.
- 这种凝结过程对于病毒DNA的整合和随后的病变产生至关重要.
- CPSF6的LLPS活动,特别是通过其MCD,在HIV-1生命周期中发挥着关键作用.
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