复旦大学Qiang Deng等研究人员合作发现，乙型肝炎病毒核心蛋白是驱动肝病进展的Rab-GAP抑制因子。2024年4月8日，《科学通报》杂志在线发表了这项成果。

研究人员建立了一种表达基本核心启动子（BCP）突变乙型肝炎病毒（HBV）基因组的转基因小鼠模型。与以往对野生型病毒的研究不同，BCP突变的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发生。值得注意的是，即使剂量很小，激动抗Fas治疗也会诱发这些小鼠的暴发性肝炎。

由于BCP突变体的HBV核心蛋白（HBc）表达量显著增加，研究人员认为HBc主动参与了肝细胞损伤。因此，HBc会干扰Fis1刺激的线粒体招募Tre-2/Bub2/Cdc16结构域家族成员15（TBC1D15）。HBc还可能通过与Rab7特异性TBC1D15和TBC1D5的保守催化结构域结合，抑制多种Rab GTPase激活蛋白。因此，在处于线粒体应激状态的细胞中，HBc 扰乱线粒体动力学，并阻止受损线粒体的再循环。此外，HBc的持续表达会通过Rab7的过度激活导致溶酶体消耗，从而进一步阻碍后期自噬，并大幅增加细胞凋亡。

最后，研究人员发现在小鼠模型中，腺病毒表达的HBc具有直接的细胞病理学作用，会造成严重的肝损伤，与抗原特异性免疫清除无关。这些发现揭示了HBc意想不到的细胞病理作用，使其成为治疗HBV相关肝病的关键靶点。BCP突变的HBV转基因小鼠也为了解慢性乙型肝炎的进展和评估治疗策略，提供了一个宝贵的模型。

研究人员表示，慢性HBV感染可导致晚期肝脏病变。

附：英文原文

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

Author: Yueqiu Gao d, Ke Lan e, Qiang Deng a b

Issue&Volume: 2024/04/08

Abstract: 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.

DOI: 10.1016/j.scib.2024.04.014

Source: https://www.sciencedirect.com/science/article/pii/S2095927324002482