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

Wei Liu, Qiyan Yao, Xiaonan Su, Yafang Deng, Mo Yang, Bo Peng, Fan Zhao, Chao Du, Xiulan Zhang, Jinsong Zhu, Daliang Wang (), Wenhui Li () and Haitao Li ()
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Wei Liu: Tsinghua University
Qiyan Yao: National Institute of Biological Sciences
Xiaonan Su: Tsinghua University
Yafang Deng: Tsinghua University
Mo Yang: National Center for Nanoscience and Technology
Bo Peng: National Institute of Biological Sciences
Fan Zhao: Tsinghua University
Chao Du: Tsinghua University
Xiulan Zhang: Tsinghua University
Jinsong Zhu: National Center for Nanoscience and Technology
Daliang Wang: Tsinghua University
Wenhui Li: National Institute of Biological Sciences
Haitao Li: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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 (HBx2–21) 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 HBx2-21, our study reveals a key role of Spindlin1 in derepressing this conserved motif, thereby promoting HBV transcription from its chromatinized genome.

Date: 2023
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DOI: 10.1038/s41467-023-40225-w

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