乙型肝炎病毒X蛋白通过共价闭合环状DNA中C-1619的DNA甲基化刺

StephenW

Mol Cells. 2018 Dec 5. doi: 10.14348/molcells.2018.0255. [Epub ahead of print]
Hepatitis B Virus X Protein Stimulates Virus Replication Via DNA Methylation of the C-1619 in Covalently Closed Circular DNA.
Lee H1, Jeong H1, Lee SY1, Kim SS1, Jang KL1.
Author information

1
    Department of Microbiology, College of Natural Science, Pusan National University, Busan 46241, Korea.

Abstract

Methylation of HBV cccDNA has been detected in vivo and in vitro; however, the mechanism and its effects on HBV replication remain unclear. HBx derived from a 1.2-mer HBV replicon upregulated protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), 3a, and 3b, resulting in methylation of the negative regulatory region (NRE) in cccDNA, while none of these effects were observed with an HBx-null mutant. The HBx-positive HBV cccDNA expressed higher levels of HBc and produced about 4-fold higher levels of HBV particles than those from the HBx-null counterpart. For these effects, HBx interrupted the action of NRE binding protein via methylation of the C-1619 within NRE, resulting in activation of the core promoter. Treatment with 5-Aza-2'dC or DNMT1 knock-down drastically impaired the ability of HBx to activate the core promoter and stimulate HBV replication in 1.2-mer HBV replicon and in vitro infection systems, indicating the positive role of HBx-mediated cccDNA methylation in HBV replication.

PMID:
    30518174
DOI:
    10.14348/molcells.2018.0255

StephenW

Mol细胞。 2018年12月5日doi：10.14348 / molcells.2018.0255。 [提前打印]
乙型肝炎病毒X蛋白通过共价闭合环状DNA中C-1619的DNA甲基化刺激病毒复制。
Lee H1，Jeong H1，Lee SY1，Kim SS1，Jang KL1。
作者信息

1
    釜山国立大学自然科学学院微生物学系，韩国釜山46241。

抽象

在体内和体外检测到HBV cccDNA的甲基化;然而，其机制及其对HBV复制的影响仍不清楚。 HBx衍生自1.2-mer HBV复制子上调DNA甲基转移酶1（DNMT1），3a和3b的蛋白质水平和酶活性，导致cccDNA中负调节区（NRE）的甲基化，而这些效应均未观察到HBx-null突变体。 HBx阳性HBV cccDNA表达较高水平的HBc，并且产生的HBV颗粒水平比HBx-null对应物高约4倍。对于这些作用，HBx通过NRE内C-1619的甲基化中断NRE结合蛋白的作用，导致核心启动子的活化。用5-Aza-2'dC或DNMT1敲低处理显着损害HBx激活核心启动子并刺激1.2-mer HBV复制子和体外感染系统中HBV复制的能力，表明HBx介导的cccDNA的阳性作用HBV复制中的甲基化。

结论：
    30518174
DOI：
    10.14348 / molcells.2018.0255