PT  - JOURNAL ARTICLE
AU  - Hou, Lidan
AU  - Zhao, Jie
AU  - Gao, Shaobing
AU  - Ji, Tong
AU  - Song, Tianyu
AU  - Li, Yining
AU  - Wang, Jingjie
AU  - Geng, Chenlu
AU  - Long, Min
AU  - Chen, Jiang
AU  - Lin, Hui
AU  - Cai, Xiujun
AU  - Cang, Yong
TI  - Restriction of hepatitis B virus replication by c-Abl–induced proteasomal degradation of the viral polymerase
AID  - 10.1126/sciadv.aau7130
DP  - 2019 Feb 01
TA  - Science Advances
PG  - eaau7130
VI  - 5
IP  - 2
4099  - http://advances.sciencemag.org/content/5/2/eaau7130.short
4100  - http://advances.sciencemag.org/content/5/2/eaau7130.full
SO  - Sci Adv2019 Feb 01; 5
AB  - 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-CRL4Cdt2 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.