Restriction of hepatitis B virus replication by c-Abl-induced proteasomal degradation of the viral polymerase

About 257 million people with chronic infection of hepatitis B virus (HBV) worldwide are at high risk of developing terminal liver diseases. Reactivation of virus replication has been frequently reported in those patient populations receiving imatinib (an Abl kinase inhibitor) or bortezomib (a prote...

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Bibliographic Details
Published in:Science advances 2019-02, Vol.5 (2), p.eaau7130-eaau7130
Main Authors: Hou, Lidan, Zhao, Jie, Gao, Shaobing, Ji, Tong, Song, Tianyu, Li, Yining, Wang, Jingjie, Geng, Chenlu, Long, Min, Chen, Jiang, Lin, Hui, Cai, Xiujun, Cang, Yong
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Diseases and Disorders
Enzyme Stability
Gene Products, pol - metabolism
Hepatitis B - metabolism
Hepatitis B - virology
Hepatitis B virus - physiology
Host-Pathogen Interactions
Humans
Models, Biological
Nuclear Proteins - metabolism
Proteasome Endopeptidase Complex - metabolism
Protein Binding
Proteolysis
Proto-Oncogene Proteins c-abl - metabolism
SciAdv r-articles
Substrate Specificity
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Virology
Virus Replication
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Summary:About 257 million people with chronic infection of hepatitis B virus (HBV) worldwide are at high risk of developing terminal liver diseases. Reactivation of virus replication has been frequently reported in those patient populations receiving imatinib (an Abl kinase inhibitor) or bortezomib (a proteasome inhibitor) to treat concurrent diseases, but the underlying mechanism for this reactivation is unknown. We report that the HBV polymerase protein is recruited by Cdt2 to the cullin-RING ligase 4 (CRL4) for ubiquitination and proteasome degradation and that this process is stimulated by the c-Abl nonreceptor tyrosine kinase. Genetic ablation of the Abl-CRL4 axis or pharmaceutical inhibition of this process stabilizes HBV polymerase protein and increases viral loads in HBV-infected liver cancer cell lines. Our study reveals a kinase-dependent activation of CRL4 ubiquitin ligase that can be targeted for blocking HBV replication.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aau7130