Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, Keppel Street, London WC1E 7HT, UK.
Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, Keppel Street, London WC1E 7HT, UK.
Cell Chem Biol. 2024 Aug 15;31(8):1518-1528.e6. doi: 10.1016/j.chembiol.2024.07.003. Epub 2024 Aug 5.
The septin cytoskeleton is primarily known for roles in cell division and host defense against bacterial infection. Despite recent insights, the full breadth of roles for septins in host defense is poorly understood. In macrophages, Shigella induces pyroptosis, a pro-inflammatory form of cell death dependent upon gasdermin D (GSDMD) pores at the plasma membrane and cell surface protein ninjurin-1 (NINJ1) for membrane rupture. Here, we discover that septins promote macrophage pyroptosis induced by lipopolysaccharide (LPS)/nigericin and Shigella infection, but do not affect cytokine expression or release. We observe that septin filaments assemble at the plasma membrane, and cleavage of GSDMD is impaired in septin-depleted cells. We found that septins regulate mitochondrial dynamics and the expression of NINJ1. Using a Shigella-zebrafish infection model, we show that septin-mediated pyroptosis is an in vivo mechanism of infection control. The discovery of septins as a mediator of pyroptosis may inspire innovative anti-bacterial and anti-inflammatory treatments.
septin 细胞骨架主要与细胞分裂和宿主抵御细菌感染有关。尽管最近有了一些新的认识，但 septin 在宿主防御中的全部作用仍知之甚少。在巨噬细胞中，志贺氏菌诱导细胞焦亡，这是一种依赖于细胞膜和细胞表面蛋白 ninjurin-1（NINJ1）上的 gasdermin D（GSDMD）孔的促炎形式的细胞死亡。在这里，我们发现 septin 促进由脂多糖（LPS）/虎红和志贺氏菌感染诱导的巨噬细胞焦亡，但不影响细胞因子的表达或释放。我们观察到 septin 纤维在质膜上组装，并且在 septin 耗尽的细胞中 GSDMD 的切割受到损害。我们发现 septin 调节线粒体动力学和 NINJ1 的表达。使用志贺氏菌-斑马鱼感染模型，我们表明 septin 介导的细胞焦亡是感染控制的一种体内机制。发现 septin 作为细胞焦亡的介质可能会激发创新的抗菌和抗炎治疗方法。
