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Restriction of hepatitis B virus replication by c-Abl–induced proteasomal degradation of the viral polymerase
Lidan Hou1,2,*, Jie Zhao3,*, Shaobing Gao1,4, Tong Ji3, Tianyu Song1,2, Yining Li1, Jingjie Wang1, Chenlu Geng1, Min Long1, Jiang Chen3, Hui Lin3, Xiujun Cai3 and Yong Cang2,†
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Science Advances 06 Feb 2019:
Vol. 5, no. 2, eaau7130
DOI: 10.1126/sciadv.aau7130
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Abstract
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.
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发表于 2019-2-7 12:44