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.
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.
Sci Bull (Beijing). 2024 Aug 30;69(16):2580-2595. doi: 10.1016/j.scib.2024.04.014. Epub 2024 Apr 8.
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.
慢性乙型肝炎病毒（HBV）感染可导致晚期肝脏病变。在这里，我们建立了一种表达基本核心启动子（BCP）突变 HBV 基因组的转基因鼠模型。与以前关于野生型病毒的研究不同，BCP 突变 HBV 转基因小鼠表现出慢性肝损伤，随着年龄的增长最终导致肝硬化和肿瘤形成。值得注意的是，激动性抗 Fas 治疗甚至在微不足道的剂量下也会在这些小鼠中引发暴发性肝炎。由于 BCP 突变体表现出 HBV 核心蛋白（HBc）表达的显著增加，我们假设 HBc 积极参与肝细胞损伤。因此，HBc 干扰 Fis1 刺激的 Tre-2/Bub2/Cdc16 结构域家族成员 15（TBC1D15）的线粒体募集。HBc 还可能通过结合其保守的催化结构域来抑制包括 Rab7 特异性 TBC1D15 和 TBC1D5 在内的多种 Rab GTPase 激活蛋白。在受到线粒体应激的细胞中，HBc 因此扰乱线粒体动力学并阻止受损线粒体的再循环。此外，持续的 HBc 表达通过 Rab7 的过度激活导致溶酶体消耗，这进一步阻碍晚期自噬并显著增加细胞凋亡。最后，我们表明，在小鼠模型中通过腺病毒表达的 HBc 具有直接的细胞病变作用，并导致严重的肝损伤，而与抗原特异性免疫清除无关。这些发现揭示了 HBc 的意想不到的细胞病变作用，使其成为治疗与 HBV 相关肝病的关键靶标。BCP 突变 HBV 转基因小鼠也为理解慢性乙型肝炎的进展和评估治疗策略提供了有价值的模型。
