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

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外文摘要：Chronic hepatitis B virus(HBV)infection can lead to advanced liver pathology.Here,we establish a trans-genic murine model expressing a basic core promoter(BCP)-mutated HBV genome.Unlike previous stud-ies 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 treat-ment.The BCP-mutated HBV transgenic mice also provide a valuable model for understanding chronic hepatitis B progression and for the assessment of therapeutic strategies.

外文关键词：

ApoptosisBasic core promoterMitophagyRab7Transgenic mice

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

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作者单位：

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

Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection,Fudan University,Shanghai 200032,China

Laboratory of Cellular Immunity,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China

Department of Infectious Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China

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基金：

Shanghai Municipal Science and Technology Major ProjectNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaInnovation Fund for Medical Sciences from Chinese Academy of Medical Sciences

项目编号：

ZD2021CY001823722338207227981871647822050552019-I2M-5-040

出版年：

2024

DOI：

10.1016/j.scib.2024.04.014

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

年,卷(期)：2024.69(16)