The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Nature. 2022 Feb;602(7897):496-502. doi: 10.1038/s41586-021-04384-4. Epub 2022 Feb 2.
Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity. Pore formation is triggered by gasdermin cleavage. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide. Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen.
Gasdermins 是一类在人类中表达的五孔形成蛋白（GSDMA-GSDME）家族，主要表达在皮肤、黏膜和免疫哨兵细胞中，是炎症细胞死亡（细胞焦亡）的关键执行者，它招募免疫细胞到感染部位并促进保护性免疫。孔形成是由 gasdermin 切割引发的。尽管已经鉴定出激活 GSDMB、C、D 和 E 的蛋白酶，但 GSDMA-皮肤中占主导地位的 gasdermin-如何被激活仍然未知。化脓性链球菌，也称为 A 组链球菌（GAS），是一种主要的皮肤病原体，在全球范围内造成大量发病率和死亡率。在这里，我们表明 GAS 半胱氨酸蛋白酶 SpeB 毒力因子通过切割 Gln246 后的 GSDMA 触发角质形成细胞细胞焦亡，释放引发细胞焦亡的活性 N 端片段。Gsdma1 基因缺陷使小鼠对 GAS 的免疫反应减弱，导致细菌不受控制的传播和死亡。GSDMA 既是 GAS SpeB 的传感器又是底物，并作为引发细胞焦亡的效应物，为宿主识别和控制危险微生物病原体的毒力添加了一个简单的单分子机制。
