Hepatitis B virus core protein as a Rab-GAP suppressor driving liver disease progression

作     者：Yu Su Fan Bu Yuanfei Zhu Le Yang Qiong Wu Yuan Zheng Jianjin Zhao Lin Yu Nan Jiang Yongxiang Wang Jian Wu Youhua Xie Xinxin Zhang Yueqiu Gao Ke Lan Qiang Deng 苏瑜;卜凡;朱园飞;杨乐;吴琼;郑缘;赵健瑾;于琳;姜楠;王勇翔;吴健;谢幼华;张欣欣;高月求;蓝柯;邓强

作者机构：Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Frontiers Science Center of Pathogenic Microorganisms and InfectionFudan UniversityShanghai 200032China Department of Infectious DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Laboratory of Cellular ImmunityShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 201203China State Key Laboratory of VirologyCollege of Life SciencesWuhan UniversityWuhan 430072China 

出 版 物：《Science Bulletin》 (科学通报（英文版）)

年 卷 期：2024年第69卷第16期

页      面：2580-2595页

核心收录：

学科分类：1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100401[医学-流行病与卫生统计学] 10[医学] 

基　　金：supported by the Shanghai Municipal Science and Technology Major Project(ZD2021CY001) the National Natural Science Foundation of China(82372233,82072279,81871647,and 82205055) the Innovation Fund for Medical Sciences from Chinese Academy of Medical Sciences(2019-I2M-5-040) 

主　　题：Apoptosis Basic core promoter Mitophagy Rab7 Transgenic mice 

摘      要：Chronic hepatitis B virus(HBV)infection can lead to advanced liver ***,we establish a transgenic murine model expressing a basic core promoter(BCP)-mutated HBV *** previous studies on the wild-type virus,the BCP-mutated HBV transgenic mice manifest chronic liver injury that culminates in cirrhosis and tumor development with ***,agonistic anti-Fas treatment induces fulminant hepatitis in these mice even at a negligible *** the BCP mutant exhibits a striking increase in HBV core protein(HBc)expression,we posit that HBc is actively involved in hepatocellular ***,HBc interferes with Fis1-stimulated mitochondrial recruitment of Tre-2/Bub2/Cdc16 domain family member 15(TBC1D15).HBc may also inhibit multiple Rab GTPase-activating proteins,including Rab7-specific TBC1D15 and TBC1D5,by binding to their conserved catalytic *** cells under mitochondrial stress,HBc thus perturbs mitochondrial dynamics and prevents the recycling of damaged ***,sustained HBc expression causes lysosomal consumption via Rab7 hyperactivation,which further hampers late-stage autophagy and substantially increases apoptotic cell ***,we show that adenovirally expressed HBc in a mouse model is directly cytopathic and causes profound liver injury,independent of antigen-specific immune *** findings reveal an unexpected cytopathic role of HBc,making it a pivotal target for HBV-associated liver disease *** BCP-mutated HBV transgenic mice also provide a valuable model for understanding chronic hepatitis B progression and for the assessment of therapeutic strategies.