Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome
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 organize...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40225-w |
| _version_ | 1797558776524439552 |
|---|---|
| author | Wei Liu Qiyan Yao Xiaonan Su Yafang Deng Mo Yang Bo Peng Fan Zhao Chao Du Xiulan Zhang Jinsong Zhu Daliang Wang Wenhui Li Haitao Li |
| author_facet | Wei Liu Qiyan Yao Xiaonan Su Yafang Deng Mo Yang Bo Peng Fan Zhao Chao Du Xiulan Zhang Jinsong Zhu Daliang Wang Wenhui Li Haitao Li |
| author_sort | Wei Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:35:10Z |
| format | Article |
| id | doaj.art-0d23e10ac08043189bda7d0a493954b3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:35:10Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-0d23e10ac08043189bda7d0a493954b32023-11-20T09:51:23ZengNature PortfolioNature Communications2041-17232023-08-0114111410.1038/s41467-023-40225-wMolecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosomeWei Liu0Qiyan Yao1Xiaonan Su2Yafang Deng3Mo Yang4Bo Peng5Fan Zhao6Chao Du7Xiulan Zhang8Jinsong Zhu9Daliang Wang10Wenhui Li11Haitao Li12State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityNational Institute of Biological SciencesState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityNational Center for Nanoscience and TechnologyNational Institute of Biological SciencesState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityNational Center for Nanoscience and TechnologyState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityNational Institute of Biological SciencesState Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, Beijing Frontier Research Center for Biological Structure, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, School of Medicine, Tsinghua UniversityAbstract 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.https://doi.org/10.1038/s41467-023-40225-w |
| spellingShingle | Wei Liu Qiyan Yao Xiaonan Su Yafang Deng Mo Yang Bo Peng Fan Zhao Chao Du Xiulan Zhang Jinsong Zhu Daliang Wang Wenhui Li Haitao Li Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome Nature Communications |
| title | Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome |
| title_full | Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome |
| title_fullStr | Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome |
| title_full_unstemmed | Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome |
| title_short | Molecular insights into Spindlin1-HBx interplay and its impact on HBV transcription from cccDNA minichromosome |
| title_sort | molecular insights into spindlin1 hbx interplay and its impact on hbv transcription from cccdna minichromosome |
| url | https://doi.org/10.1038/s41467-023-40225-w |
| work_keys_str_mv | AT weiliu molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT qiyanyao molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT xiaonansu molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT yafangdeng molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT moyang molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT bopeng molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT fanzhao molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT chaodu molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT xiulanzhang molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT jinsongzhu molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT daliangwang molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT wenhuili molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome AT haitaoli molecularinsightsintospindlin1hbxinterplayanditsimpactonhbvtranscriptionfromcccdnaminichromosome |