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

Yu Su ¹Fan Bu ¹Yuanfei Zhu ²Le Yang ¹Qiong Wu ¹Yuan Zheng ¹Jianjin Zhao ¹Lin Yu ¹Nan Jiang ¹Yongxiang Wang ³Jian Wu ³Youhua Xie ¹Xinxin Zhang ⁴Yueqiu Gao ⁵Ke Lan ⁶Qiang Deng¹

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作者信息

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;Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection,Fudan University,Shanghai 200032,China
2. 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
3. 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
4. Department of Infectious Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China
5. Laboratory of Cellular Immunity,Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China
6. State Key Laboratory of Virology,College of Life Sciences,Wuhan University,Wuhan 430072,China
折叠

Abstract

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.

Key words

Apoptosis/Basic core promoter/Mitophagy/Rab7/Transgenic mice

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基金项目

Shanghai Municipal Science and Technology Major Project(ZD2021CY001)

National Natural Science Foundation of China(82372233)

National Natural Science Foundation of China(82072279)

National Natural Science Foundation of China(81871647)

National Natural Science Foundation of China(82205055)

Innovation Fund for Medical Sciences from Chinese Academy of Medical Sciences(2019-I2M-5-040)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

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