Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome

• Published in: Nature communications 2023-08, Vol.14 (1), p.4663-4663, Article 4663
• Main Authors: Liu, Wei, Yao, Qiyan, Su, Xiaonan, Deng, Yafang, Yang, Mo, Peng, Bo, Zhao, Fan, Du, Chao, Zhang, Xiulan, Zhu, Jinsong, Wang, Daliang, Li, Wenhui, Li, Haitao
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/89; 14/63; 38/15; 38/22; 38/23; 38/44; 45/70; 45/77; 45/88; 45/90; 631/326/596/1550; 631/337/100/2285; 631/337/176; 631/45/535/1266; 82/75; 82/80; 82/83; Chronic infection; Circular DNA; Conserved sequence; Epigenetics; Gene expression; Genomes; Hepatitis B; Heterochromatin; Histone H3; Histones; Humanities and Social Sciences; Life cycles; Methylation; multidisciplinary; Proteins; Science; Science (multidisciplinary); Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40225-w

Molecular interplay between host epigenetic factors and viral proteins constitutes an intriguing mechanism for sustaining hepatitis B virus (HBV) life cycle and its chronic infection. HBV encodes a regulatory protein, HBx, which activates transcription and replication of HBV genome organized as covalently closed circular (ccc) DNA minichromosome. Here we illustrate how HBx accomplishes its task by hijacking Spindlin1, an epigenetic reader comprising three consecutive Tudor domains. Our biochemical and structural studies have revealed that the highly conserved N-terminal 2–21 segment of HBx (HBx 2–21 ) associates intimately with Tudor 3 of Spindlin1, enhancing histone H3 “K4me3-K9me3” readout by Tudors 2 and 1. Functionally, Spindlin1-HBx engagement promotes gene expression from the chromatinized cccDNA, accompanied by an epigenetic switch from an H3K9me3-enriched repressive state to an H3K4me3-marked active state, as well as a conformational switch of HBx that may occur in coordination with other HBx-binding factors, such as DDB1. Despite a proposed transrepression activity of HBx 2-21 , our study reveals a key role of Spindlin1 in derepressing this conserved motif, thereby promoting HBV transcription from its chromatinized genome. The mechanism by which the chromatinized HBV genome is transcribed remains poorly understood. In this study, Liu et al. demonstrate how HBx exploits Spindlin1, a histone methylation reader, to overcome heterochromatin barriers and enhance HBV transcription from the cccDNA minichromosome.