全球真菌-宿主互动图谱识别了候选素的宿主目标
Tian-Yi Zhang1, Yao-Qi Chen1, Jing-Cong Tan1
1State Key Laboratory of Systems Medicine for Cancer, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Nature communications
|February 27, 2024
概括
来自Candida albicans的真菌毒素candyalysin通过准CCNH来劫持DNA损伤修复途径. 这种相互作用抑制了修复,促进了真菌感染和DNA断裂.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- kandidatalysin 是一种常见的真菌病原体Candida albicans的关键毒素.
- 其精确的细胞内标和宿主细胞中的机制仍然不完全理解.
- 了解这些相互作用对于开发有针对性的抗真菌疗法至关重要.
研究的目的:
- 通过使用高通量选方法,识别出candidalysin的直接人体蛋白相互作用体.
- 为了阐明候选素在宿主DNA损伤反应途径中的作用.
- 调查针对候选酶-CCNH相互作用的治疗潜力.
主要方法:
- 高通量增强的酵母双杂交 (HT-eY2H) 选,以映射候选溶解中的相互作用组.
- 涉及DNA双链断裂 (DSB) 试验 (γ-H2AX焦点) 的机制研究.
- 共同免疫沉和西部斑点,以确认蛋白质相互作用和通路激活.
- 在活体研究中,使用了小鼠模型的口腔喉疹病.
主要成果:
- 鉴定了CCNH (环素H),CDK激活激酶 (CAK) 综合体的组成部分,作为candidatalysin的直接宿主标.
- 证明,通过准CCNH和激活CAK,甘地利辛会诱导显著的双链DNA断裂 (DSB),从而抑制DNA修复.
- 显示CCNH功能的丧失减轻了候选素诱导的DSB,其耗尽在体内阻止了DSB.
结论:
- 坎迪达利辛通过与CCNH的直接相互作用,积极劫持宿主的正规DNA损伤修复途径.
- 这种劫持机制通过抑制DNA修复和增加DNA损伤来促进真菌病原性.
- 针对候选酶-CCNH相互作用,为对抗Candida albicans感染提供了一个潜在的策略.
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