Group A Streptococcus (GAS) is among the top ten causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections, including necrotizing fasciitis and toxic shock syndrome. Here, we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine interleukin-1β (IL-1β) and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K⁺ efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.

中文翻译：

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A组链球菌M蛋白激活NLRP3炎性小体。

A组链球菌（GAS）是人类感染相关死亡率的十大原因之一。M蛋白是最丰富的GAS表面蛋白，M1血清型GAS菌株与侵袭性感染相关，包括坏死性筋膜炎和中毒性休克综合症。在这里，我们报道释放的可溶性M1蛋白在巨噬细胞（Mϕ）中触发了程序性细胞死亡。M1作为caspase-1依赖的NLRP3炎性小体激活，诱导促炎细胞因子白介素1β（IL-1β）和巨噬细胞焦化的成熟和释放的第二信号。M1的结构动态B重复结构域对于炎症小体激活至关重要，涉及K ⁺网格蛋白介导的胞吞作用使外排和M1蛋白内在化。小鼠腹膜内攻击显示可溶性M1对IL-1β激活是足够的和特异性的，这可能是激活宿主针对病原体的免疫力的预警。相反，在全身感染中，与M1介导的细胞凋亡和IL-1β释放相关的过度炎症会加重组织损伤。