HIRA Supports Hepatitis B Virus Minichromosome Establishment and Transcriptional Activity in Infected Hepatocytes.
HIRA Supports Hepatitis B Virus Minichromosome Establishment and Transcriptional Activity in Infected Hepatocytes.
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DOI：
10.1016/j.jcmgh.2022.05.007
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发表时间：
2022
影响因子：
7.2
通讯作者：
Zoulim, Fabien
中科院分区：
文献类型：
--
作者：
Locatelli, Maelle;Quivy, Jean-Pierre;Chapus, Fleur;Michelet, Maud;Fresquet, Judith;Maadadi, Sarah;Aberkane, Amel Neila;Diederichs, Audrey;Lucifora, Julie;Rivoire, Michel;Almouzn, Genevieve;Testoni, Barbara;Zoulim, Fabien
乙型肝炎病毒 (HBV) 感染后，部分双链病毒 DNA 转化为共价闭合的环状染色质附加型结构 (cccDNA)。这种形式代表了负责病毒在受感染肝脏中持续存在的长寿命基因组库。尽管宿主细胞 DNA 损伤反应参与 cccDNA 的形成已被证实，但这项工作研究了人类肝细胞感染早期阶段 cccDNA 上尚未确定的组蛋白动态。在自然感染的细胞培养模型（即 Na+-牛磺胆酸共转运多肽 (NTCP) 过表达 HepG2 细胞，HepG2hNTCP）和感染 HBV 的原代人肝细胞中，通过 cccDNA 特异性染色质免疫沉淀和病毒微染色体建立和病毒转录开始的早期动力学过程中的功能丧失实验，对宿主染色质相关因子进行了详细研究。我们的结果表明，cccDNA 的形成需要通过组蛋白调节剂 A (HIRA) 依赖性途径沉积组蛋白变体 H3.3。这与 cccDNA 前体的修复同时发生，并且独立于从头病毒蛋白表达。此外，S31磷酸化形式的H3.3似乎是在受感染的培养细胞和人类肝脏中转录活性cccDNA上发现的优先H3变体。 cccDNA 库建立后 HIRA 耗尽表明病毒转录和 RNA 生产需要 HIRA 募集。总而言之，我们证明了 HIRA 在 HBV 基因组和宿主细胞机制之间的相互作用中发挥着至关重要的作用，以确保受感染肝细胞中病毒微型染色体的形成和活跃转录。
Upon hepatitis B virus (HBV) infection, partially double-stranded viral DNA converts into a covalently closed circular chromatinized episomal structure (cccDNA). This form represents the long-lived genomic reservoir responsible for viral persistence in the infected liver. Although the involvement of host cell DNA damage response in cccDNA formation has been established, this work investigated the yet-to-be-identified histone dynamics on cccDNA during early phases of infection in human hepatocytes. Detailed studies of host chromatin-associated factors were performed in cell culture models of natural infection (ie, Na+-taurocholate cotransporting polypeptide (NTCP)-overexpressing HepG2 cells, HepG2hNTCP) and primary human hepatocytes infected with HBV, by cccDNA-specific chromatin immunoprecipitation and loss-of-function experiments during early kinetics of viral minichromosome establishment and onset of viral transcription. Our results show that cccDNA formation requires the deposition of the histone variant H3.3 via the histone regulator A (HIRA)-dependent pathway. This occurs simultaneously with repair of the cccDNA precursor and independently from de novo viral protein expression. Moreover, H3.3 in its S31 phosphorylated form appears to be the preferential H3 variant found on transcriptionally active cccDNA in infected cultured cells and human livers. HIRA depletion after cccDNA pool establishment showed that HIRA recruitment is required for viral transcription and RNA production. Altogether, we show a crucial role for HIRA in the interplay between HBV genome and host cellular machinery to ensure the formation and active transcription of the viral minichromosome in infected hepatocytes.
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影响因子：
6.7
作者：
Kitamura K;Que L;Shimadu M;Koura M;Ishihara Y;Wakae K;Nakamura T;Watashi K;Wakita T;Muramatsu M
通讯作者：
Muramatsu M
影响因子：
14.9
作者：
Saper G;Kler S;Asor R;Oppenheim A;Raviv U;Harries D
通讯作者：
Harries D
影响因子：
4.9
作者：
Ladner, SK;Otto, MJ;King, RW
通讯作者：
King, RW
DOI：
10.1073/pnas.1409986111
发表时间：
2014-10-07
影响因子：
11.1
作者：
Koeniger, Christian;Wingert, Ida;Nassal, Michael
通讯作者：
Nassal, Michael
影响因子：
25.7
作者：
Lucifora, Julie;Arzberger, Silke;Protzer, Ulrike
通讯作者：
Protzer, Ulrike