A nucleosome switch primes hepatitis B virus infection

IF 42.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Pub Date : 2025-02-20 DOI:10.1016/j.cell.2025.01.033

Nicholas A. Prescott, Tracy Biaco, Andrés Mansisidor, Yaron Bram, Justin Rendleman, Sarah C. Faulkner, Abigail A. Lemmon, Christine Lim, Rachel Tiersky, Eralda Salataj, Liliana Garcia-Martinez, Rodrigo L. Borges, Lluis Morey, Pierre-Jacques Hamard, Richard P. Koche, Viviana I. Risca, Robert E. Schwartz, Yael David

{"title":"A nucleosome switch primes hepatitis B virus infection","authors":"Nicholas A. Prescott, Tracy Biaco, Andrés Mansisidor, Yaron Bram, Justin Rendleman, Sarah C. Faulkner, Abigail A. Lemmon, Christine Lim, Rachel Tiersky, Eralda Salataj, Liliana Garcia-Martinez, Rodrigo L. Borges, Lluis Morey, Pierre-Jacques Hamard, Richard P. Koche, Viviana I. Risca, Robert E. Schwartz, Yael David","doi":"10.1016/j.cell.2025.01.033","DOIUrl":null,"url":null,"abstract":"Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings <em>in situ</em> and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"20 1","pages":""},"PeriodicalIF":42.5000,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cell.2025.01.033","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

核小体开关引发乙型肝炎病毒感染

慢性乙型肝炎病毒（HBV）感染是一种无法治愈的病原体，可引起肝脏疾病和肝细胞癌。在感染发生过程中，HBV建立了一个独立的小染色体，由病毒共价闭合环状DNA （cccDNA）基因组和宿主组蛋白组成。病毒X基因必须在感染后立即表达，以诱导宿主沉默因子Smc5/6复合物的降解。然而，cccDNA染色化与X基因转录之间的关系尚不清楚。通过构建重组病毒小染色体平台，我们发现核小体在cccDNA中的占用调节X的转录。我们原位证实了这些发现，并进一步表明染色质不稳定分子CBL137抑制全长X转录和乙肝病毒在原代人肝细胞中的感染。我们的结果揭示了一个长期存在的悖论，并代表了治疗慢性HBV感染的潜在治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.