Laboratory of Molecular Cell Biology, Graduate School of Medicine, College of Medicine, Korea University, Seoul 02841, Republic of Korea.
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
Biochim Biophys Acta Biomembr. 2019 Apr 1;1861(4):729-737. doi: 10.1016/j.bbamem.2019.01.006. Epub 2019 Jan 16.
Hepatitis B virus X protein (HBx) functions in a variety of cellular events during the HBV life cycle. In a previous study, we reported that the HBx protein is sufficient to induce mitochondrial membrane permeabilization; however, the exact mechanism of HBx-induced mitochondrial membrane permeabilization has been not proposed. In this study, we report that HBx specifically targets cardiolipin (CL) and induces membrane permeabilization depending on CL concentration in mitochondrial outer membrane-mimic artificial liposomes. Interestingly, HBx-induced membrane permeabilization was enhanced by liposomes containing phosphatidylethanolamine, which plays a crucial role in forming a negative curvature on the membrane. We also show that the 68-117 region of HBx, which interacts with mitochondria, is necessary for membrane permeabilization. We examined the size of the pores formed by HBx and found that HBx permeates fluorescent dyes depending on the hydrodynamic diameter with a pore size of approximately 10 nm. The results of this study suggest that CL is necessary for HBx-induced membrane permeabilization and provide important information that suggests a new strategy for anti-HBV therapy.
乙型肝炎病毒 X 蛋白 (HBx) 在 HBV 生命周期中的各种细胞事件中发挥作用。在之前的研究中，我们报告 HBx 蛋白足以诱导线粒体膜通透性；然而，HBx 诱导的线粒体膜通透性的确切机制尚未提出。在这项研究中，我们报告 HBx 特异性靶向心磷脂 (CL)，并根据线粒体外膜模拟人工脂质体中的 CL 浓度诱导膜通透性。有趣的是，含有磷脂酰乙醇胺的脂质体增强了 HBx 诱导的膜通透性，磷脂酰乙醇胺在膜上形成负曲率方面起着至关重要的作用。我们还表明，与线粒体相互作用的 HBx 的 68-117 区域对于膜通透性是必需的。我们检查了由 HBx 形成的孔的大小，发现 HBx 根据流体动力学直径渗透荧光染料，孔的大小约为 10nm。这项研究的结果表明 CL 对于 HBx 诱导的膜通透性是必要的，并提供了重要的信息，为抗 HBV 治疗提供了新的策略。
