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通过NSUN2介导的HBVRNA的m5C修饰积极调节HBV复制

Jiangpeng Feng¹, Tianmo Xu^1,2, Miao He^1,3

¹State Key Laboratory of Virology, RNA Institute, College of Life Sciences and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.

|December 4, 2023

概括

乙型肝炎病毒 (HBV) RNA 5-甲基细胞因子 (m5C) 修饰由NSUN2通过稳定RNA增强病毒复制. 这项研究确定了关键的m5C位点,并揭示了HBV和NSUN2.2之间的积极反循环.

科学领域:

病毒学病毒学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
分子生物学分子生物学

背景情况:

慢性乙型肝炎病毒 (HBV) 感染仍然是一个重大的全球健康挑战,导致肝硬化和癌症.
表观遗传修饰,包括N6-甲基氨酸 (m6A) 和5-甲基氨酸 (m5C),越来越多地被认为是它们在病毒生命周期中的作用.
对于m5C修饰在HBVRNA及其相关酶在病毒复制中的特定作用尚不清楚.

研究的目的:

研究m5C甲基转移酶和甲基转移酶在HBV生命周期中的作用.
在HBVRNA上识别和描述m5C修饰位.
阐明m5C修饰影响HBVRNA稳定性和复制的机制.

主要方法:

实验室双硫酸盐测序和高通量双硫酸盐测序被用来绘制HBVRNA上的m5C位点.
用于评估m5C修饰对HBV表达和复制的影响,使用了局部定向突变发生.
在细胞系 (HepG2-NTCP,PHHs) 和小鼠模型 (C57BL/6JGpt-Nsun2+/-) 中进行了NSUN2淘汰实验,以评估对HBV复制的影响.

主要成果:

缺乏m5C甲基转移酶NSUN2会对HBV表达产生负面调节,而缺乏甲基转移酶TET2则对HBV表达产生正面调节.
在HBVRNA上确定了两个关键的m5C位点 (C2017和C131),突变影响HBV表达和复制.
发现NSUN2介导的m5C修饰增强了HBVRNA的稳定性,促进了病毒复制.
在HBV表达和核心蛋白调高内源NSUN2表达的地方观察到一个积极的反循环.

结论:

在保持RNA稳定性和积极调节HBV复制方面,NSUN2介导的m5C修改HBVRNA至关重要.
该研究为HBVRNA提供了高分辨率的m5C配置文件,识别了关键的调节部位.
准NSUN2-m5C相互作用是针对慢性HBV感染的潜在治疗策略.

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