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

乙型肝炎病毒核心蛋白通过抑制Rab-GAP促进肝病进展

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

机构地区：[1]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),School of Basic Medical Sciences,Shanghai Institute of Infectious Disease and Biosecurity,Fudan University,Shanghai 200032,China [2]Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection,Fudan University,Shanghai 200032,China [3]Department of Infectious Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [4]Laboratory of Cellular Immunity,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [5]State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China

出　　处：《Science Bulletin》2024年第16期2580-2595,共16页科学通报（英文版）

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).

摘　　要：Chronic hepatitis B virus(HBV)infection can lead to advanced liver pathology.Here,we establish a transgenic murine model expressing a basic core promoter(BCP)-mutated HBV genome.Unlike 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 age.Notably,agonistic anti-Fas treatment induces fulminant hepatitis in these mice even at a negligible dose.As the BCP mutant exhibits a striking increase in HBV core protein(HBc)expression,we posit that HBc is actively involved in hepatocellular injury.Accordingly,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 domain.In cells under mitochondrial stress,HBc thus perturbs mitochondrial dynamics and prevents the recycling of damaged mitochondria.Moreover,sustained HBc expression causes lysosomal consumption via Rab7 hyperactivation,which further hampers late-stage autophagy and substantially increases apoptotic cell death.Finally,we show that adenovirally expressed HBc in a mouse model is directly cytopathic and causes profound liver injury,independent of antigen-specific immune clearance.These findings reveal an unexpected cytopathic role of HBc,making it a pivotal target for HBV-associated liver disease treatment.The BCP-mutated HBV transgenic mice also provide a valuable model for understanding chronic hepatitis B progression and for the assessment of therapeutic strategies.

关 键 词：APOPTOSIS Basic core promoter MITOPHAGY Rab7 Transgenic mice 

分 类 号：R512.62[医药卫生—内科学]