HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver

Yuan, Hongfeng; Zhao, Lina; Yuan, Ying; Yun, Haolin; Zheng, Wei; Geng, Yu; Yang, Guang; Wang, Yufei; Zhao, Man; Zhang, Xiaodong

doi:10.7150/thno.57531

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Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

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Theranostics 2021; 11(17):8362-8378. doi:10.7150/thno.57531 This issue Cite

Research Paper

HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver

Hongfeng Yuan^1,2#, Lina Zhao^2#, Ying Yuan^2#, Haolin Yun², Wei Zheng², Yu Geng², Guang Yang¹, Yufei Wang², Man Zhao², Xiaodong Zhang^1✉

1. Department of Gastrointestinal Cancer Biology, Tianjin Cancer Institute, Liver Cancer Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, P.R. China.
2. Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, P.R. China.
# Hongfeng Yuan, Lina Zhao, and Ying Yuan contributed equally as joint first authors.

Citation:

Yuan H, Zhao L, Yuan Y, Yun H, Zheng W, Geng Y, Yang G, Wang Y, Zhao M, Zhang X. HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver. Theranostics 2021; 11(17):8362-8378. doi:10.7150/thno.57531. https://www.thno.org/v11p8362.htm

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Abstract

Rationale: Hepatitis B x protein (HBx) is required to initiate and maintain the replication of hepatitis B virus (HBV). Protein arginine methyltransferases 5 (PRMT5) negatively regulates HBV transcription. WD repeat domain 77 protein (WDR77) greatly enhances the methyltransferase activity of PRMT5. However, the role of WDR77 in the modulation of cccDNA transcription and HBV replication is poorly understood. In this study, we investigated the mechanism by which HBx modulated HBV replication involving WDR77 in the liver.

Methods: A human liver-chimeric mouse model was established. Immunohistochemistry (IHC) staining, Western blot analysis, Southern blot analysis, Northern blot analysis, immunofluorescence assays, ELISA, RT-qPCR, CoIP assays, and ChIP assays were performed in human liver-chimeric mouse model, primary human hepatocytes (PHHs), HepG2-NTCP, dHepaRG and HepG2 cell lines.

Results: HBV infection and HBx expression remarkably reduced the protein levels of WDR77 in human liver-chimeric mice and HepG2-NTCP cells. WDR77 restricted cccDNA transcription and HBV replication in PHHs and HepG2-NTCP cells. Mechanically, WDR77 enhanced PRMT5-triggered symmetric dimethylation of arginine 3 on H4 (H4R3me2s) on the cccDNA minichromosome to control cccDNA transcription. HBx drove the cellular DDB1-containing E3 ubiquitin ligase to degrade WDR77 through recruiting WDR77, leading to the disability of methyltransferase activity of PRMT5. Thus, HBx promoted HBV replication by driving a positive feedback loop of HBx-DDB1/WDR77/PRMT5/H4R3me2s/cccDNA/HBV/HBx in the liver.

Conclusions: HBx attenuates the WDR77-mediated HBV repression by driving DDB1-induced WDR77 degradation in the liver. Our finding provides new insights into the mechanism by which HBx enhances HBV replication in the liver.

Keywords: HBx, H4R3me2s, WDR77, PRMT5, DDB1

Citation styles

APA

Yuan, H., Zhao, L., Yuan, Y., Yun, H., Zheng, W., Geng, Y., Yang, G., Wang, Y., Zhao, M., Zhang, X. (2021). HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver. Theranostics, 11(17), 8362-8378. https://doi.org/10.7150/thno.57531.

ACS

Yuan, H.; Zhao, L.; Yuan, Y.; Yun, H.; Zheng, W.; Geng, Y.; Yang, G.; Wang, Y.; Zhao, M.; Zhang, X. HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver. Theranostics 2021, 11 (17), 8362-8378. DOI: 10.7150/thno.57531.

NLM

CSE

Yuan H, Zhao L, Yuan Y, Yun H, Zheng W, Geng Y, Yang G, Wang Y, Zhao M, Zhang X. 2021. HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver. Theranostics. 11(17):8362-8378.

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