Institute of Medical Microbiology and Hygiene, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
Institute for Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Johann-Joachim Becher-Weg 30, 55128 Mainz, Germany.
Biol Chem. 2019 Sep 25;400(10):1261-1276. doi: 10.1515/hsz-2018-0472.
The small β-pore-forming α-toxin, also termed α-hemolysin or Hla is considered to be an important virulence factor of Staphylococcus aureus. Perforation of the plasma membrane (PM) by Hla leads to uncontrolled flux of ions and water. Already a small number of toxin pores seems to be sufficient to induce complex cellular responses, many of which depend on the efflux of potassium. In this article, we discuss the implications of secondary membrane lesions, for example, by endogenous channels, for Hla-mediated toxicity, for calcium-influx and membrane repair. Activation of purinergic receptors has been proposed to be a major contributor to the lytic effects of various pore forming proteins, but new findings raise doubts that this holds true for Hla. However, the recently discovered cellular pore forming proteins gasdermin D and Mixed lineage kinase domain-like pseudokinase (MLKL) which perforate the PM from the cytosolic side might contribute to both calcium-influx-dependent damage and membrane repair. Activation of endogenous pore forming proteins by Hla above a threshold concentration could explain the apparent dependence of pore characteristics on toxin concentrations. If secondary membrane damage in the aftermath of Hla-attack contributes significantly to overall PM permeability, it might be an interesting target for new therapeutic approaches.
小 β 孔形成 α 毒素，也称为 α-溶血素或 Hla，被认为是金黄色葡萄球菌的重要毒力因子。Hla 对质膜 (PM) 的穿孔导致离子和水的不可控流动。已经有少量的毒素孔似乎足以诱导复杂的细胞反应，其中许多反应依赖于钾的外流。在本文中，我们讨论了次级膜损伤（例如，由内源性通道引起的损伤）对 Hla 介导的毒性、钙内流和膜修复的影响。嘌呤能受体的激活被认为是各种孔形成蛋白裂解作用的主要贡献者，但新的发现让人怀疑这是否适用于 Hla。然而，最近发现的细胞孔形成蛋白 gasdermin D 和混合谱系激酶结构域样假激酶 (MLKL) 从细胞质侧穿孔质膜，可能有助于钙依赖性损伤和膜修复。Hla 超过阈值浓度时激活内源性孔形成蛋白，可以解释孔特性对毒素浓度的明显依赖性。如果 Hla 攻击后次级膜损伤对总 PM 通透性有重要贡献，那么它可能是新治疗方法的一个有趣靶点。
