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Cited by 44Hepatitis B Virus StudiesGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

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

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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·2023·Nature Communications
DOI 10.1038/s41467-023-40225-wPMC PMC10400593

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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 (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.

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Research works printed but not linked: 48

  1. Revill, P., Testoni, B., Locarnini, S. & Zoulim, F. Global strategies are required to cure and eliminate HBV infection. Nat. Rev. Gastroenterol. Hepatol. 13, 239–248 (2016). · DOI
  2. Scaglione, S. J. & Lok, A. S. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology 142, 1360–1368.e1361 (2012). · DOI
  3. Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049 (2012). · DOI
  4. Bock, C. T., Schranz, P., Schroder, C. H. & Zentgraf, H. Hepatitis-B Virus genome is organized into nucleosomes in the nucleus of the infected cell. Virus Genes 8, 215–229 (1994). · DOI
  5. Bock, C. T. et al. Structural organization of the hepatitis B virus minichromosome. J. Mol. Biol. 307, 183–196 (2001). · DOI
  6. Belloni, L. et al. Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function. Proc. Natl. Acad. Sci. USA 106, 19975–19979 (2009). · DOI
  7. Lucifora, J. et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221–1228 (2014). · DOI
  8. Nassal, M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64, 1972–1984 (2015). · DOI
  9. van Breugel, P. C. et al. Hepatitis B virus X protein stimulates gene expression selectively from extrachromosomal DNA templates. Hepatology 56, 2116–2124 (2012). · DOI
  10. Mitra, B. & Guo, H. Hepatitis B virus X protein crosses out Smc5/6 complex to maintain covalently closed circular DNA transcription. Hepatology 64, 2246–2249 (2016). · DOI
  11. Hodgson, A. J., Hyser, J. M., Keasler, V. V., Cang, Y. & Slagle, B. L. Hepatitis B virus regulatory HBx protein binding to DDB1 is required but is not sufficient for maximal HBV replication. Virology 426, 73–82 (2012). · DOI
  12. Li, T., Robert, E. I., van Breugel, P. C., Strubin, M. & Zheng, N. A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat. Struct. Mol. Biol. 17, 105–111 (2010). · DOI
  13. Decorsiere, A. et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature 531, 386–389 (2016). · DOI
  14. Murphy, C. M. et al. Hepatitis B Virus X protein promotes degradation of SMC5/6 to enhance HBV replication. Cell Rep. 16, 2846–2854 (2016). · DOI
  15. Tsai, K. & Cullen, B. R. Epigenetic and epitranscriptomic regulation of viral replication. Nat. Rev. Microbiol. 18, 559–570 (2020). · DOI
  16. Zhang, T. Y. et al. Structural and functional analyses of hepatitis B virus X protein BH3-like domain and Bcl-xL interaction. Nat. Commun. 10, 3192 (2019).
  17. Jiang, T., Liu, M., Wu, J. & Shi, Y. Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx. Proc. Natl. Acad. Sci. USA 113, 2074–2079 (2016). · DOI
  18. Benhenda, S. et al. Methyltransferase PRMT1 is a binding partner of HBx and a negative regulator of hepatitis B virus transcription. J. Virol. 87, 4360–4371 (2013). · DOI
  19. Cougot, D. et al. Inhibition of PP1 phosphatase activity by HBx: a mechanism for the activation of hepatitis B virus transcription. Sci. Signal. 5, ra1 (2012). · DOI
  20. Riviere, L. et al. HBx relieves chromatin-mediated transcriptional repression of hepatitis B viral cccDNA involving SETDB1 histone methyltransferase. J. Hepatol. 63, 1093–1102 (2015). · DOI
  21. Alarcon, V. et al. The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state. Sci. Rep. 6, 25901 (2016). · DOI
  22. Tropberger, P. et al. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc. Natl. Acad. Sci. USA 112, E5715–E5724 (2015). · DOI
  23. Peng, B. et al. Nonproductive hepatitis B virus covalently closed circular DNA generates HBx-related transcripts from the HBx/Enhancer I region and acquires reactivation by superinfection in single cells. J. Virol. 97, e0171722 (2023). · DOI
  24. Ducroux, A. et al. The Tudor domain protein Spindlin1 is involved in intrinsic antiviral defense against incoming hepatitis B virus and herpes simplex virus type 1. PLoS Pathog. 10, e1004343 (2014). · DOI
  25. Zhao, Q. et al. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J. Biol. Chem. 282, 647–656 (2007). · DOI
  26. Yang, N. et al. Distinct mode of methylated lysine-4 of histone H3 recognition by tandem tudor-like domains of Spindlin1. Proc. Natl. Acad. Sci. USA 109, 17954–17959 (2012). · DOI
  27. Wang, W. et al. Nucleolar protein Spindlin1 recognizes H3K4 methylation and stimulates the expression of rRNA genes. EMBO Rep. 12, 1160–1166 (2011). · DOI
  28. Su, X. et al. Molecular basis underlying histone H3 lysine-arginine methylation pattern readout by Spin/Ssty repeats of Spindlin1. Genes Dev. 28, 622–636 (2014). · DOI
  29. Zhao, F. et al. Molecular basis for histone H3 “K4me3-K9me3/2” methylation pattern readout by Spindlin1. J. Biol. Chem. 295, 16877–16887 (2020). · DOI
  30. Du, Y. et al. Structural mechanism of bivalent histone H3K4me3K9me3 recognition by the Spindlin1/C11orf84 complex in rRNA transcription activation. Nat. Commun. 12, 949 (2021).
  31. Zhao, F. et al., Molecular basis for SPIN·DOC-Spindlin1 engagement and its role in transcriptional inhibition. Preprint at https://doi.org/10.1101/2021.03.07.432812 (2021). · DOI
  32. Wang, J. X. et al. SPINDLIN1 promotes cancer cell proliferation through activation of WNT/TCF-4 signaling. Mol. Cancer Res. 10, 326–335 (2012). · DOI
  33. Franz, H. et al. The histone code reader SPIN1 controls RET signaling in liposarcoma. Oncotarget 6, 4773–4789 (2015). · DOI
  34. Kumar, V., Jayasuryan, N. & Kumar, R. A truncated mutant (residues 58-140) of the hepatitis B virus X protein retains transactivation function. Proc. Natl. Acad. Sci. USA 93, 5647–5652 (1996). · DOI
  35. Tang, H., Oishi, N., Kaneko, S. & Murakami, S. Molecular functions and biological roles of hepatitis B virus x protein. Cancer Sci. 97, 977–983 (2006). · DOI
  36. Ramakrishnan, D. et al. Hepatitis B Virus X protein function requires zinc binding. J. Virol. 93, e00250–19 (2019). · DOI
  37. Zhao, S. et al. Plant HP1 protein ADCP1 links multivalent H3K9 methylation readout to heterochromatin formation. Cell Res. 29, 54–66 (2019). · DOI
  38. Giglione, C., Boularot, A. & Meinnel, T. Protein N-terminal methionine excision. Cell. Mol. Life Sci. 61, 1455–1474 (2004). · DOI
  39. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein-protein interfaces. J. Mol. Biol. 234, 946–950 (1993). · DOI
  40. Hirai, H., Takemata, N., Tamura, M. & Ohta, K. Facultative heterochromatin formation in rDNA is essential for cell survival during nutritional starvation. Nucleic Acids Res. 50, 3727–3744 (2022). · DOI
  41. Misra, K. P., Mukherji, A. & Kumar, V. The conserved amino-terminal region (amino acids 1-20) of the hepatitis B virus X protein shows a transrepression function. Virus Res. 105, 157–165 (2004). · DOI
  42. Zheng, D. L. et al. Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A. J. Hepatol. 50, 377–387 (2009). · DOI
  43. Zhao, S. et al. Kinetic and high-throughput profiling of epigenetic interactions by 3D-carbene chip-based surface plasmon resonance imaging technology. Proc. Natl. Acad. Sci. USA 114, E7245–E7254 (2017).
  44. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997). · DOI · Paper page
  45. Vagin, A. & Teplyakov, A. Molecular replacement with MOLREP. Acta Crystallogr. D Biol. Crystallogr. 66, 22–25 (2010). · DOI
  46. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132 (2004). · DOI · Paper page
  47. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010). · DOI · Paper page
  48. Patel, A. et al. Automethylation activities within the mixed lineage leukemia-1 (MLL1) core complex reveal evidence supporting a “two-active site” model for multiple histone H3 lysine 4 methylation. J. Biol. Chem. 289, 868–884 (2014). · DOI

Metadata

Authors
Liu, W., Yao, Q., Su, X., Deng, Y., Yang, M., Peng, B., Zhao, F., Du, C., Zhang, X., Zhu, J., Wang, D., Li, W., & Li, H.
Affiliations
  • Center for Life Sciences (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • State Key Laboratory of Molecular Oncology (CN)
  • National Cancer Institute (US)
  • National Institute of Biological Sciences, Beijing (CN)
  • National Center for Nanoscience and Technology (CN)
Corresponding author
  • Wang, Daliang
  • Li, Wenhui
  • Li, Haitao
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-08-03
Volume
14
Issue
1
Pages
4663-4663
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-40225-w
PMC
PMC10400593
OpenAlex
W4385554457
Cited by
44
References
1
Citations by year
2026: 12 · 2025: 16 · 2024: 13 · 2023: 3
FWCI
8.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81773030, 92153302, 31725014, 81525018, 32000447)
Topics
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
HBx, hepatitis B virus, HBV transcription, Tudor domain, H3K4me3, H3K9me3, DDB1, host-virus interaction, chronic hepatitis B
MeSH terms
DNA, Circular, DNA, Viral, Hepatitis B virus, Microtubule-Associated Proteins, Phosphoproteins, Virus Replication, Trans-Activators, Cell Cycle Proteins, Viral Regulatory and Accessory Proteins

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