Gasdermin家族蛋白介导的细胞焦亡及其病理作用与靶向干预

Gasdermin-Mediated Pyroptosis and Its Pathological Roles and Targeted Intervention

细胞焦亡是一种程序性的炎性细胞死亡,关键执行分子是gasdermin家族蛋白。在细胞感知危险信号后,gasdermin发生剪切活化,释放出具有成孔活性的N端结构域,这一结构域与细胞膜磷脂结合并寡聚化形成稳定的膜孔洞结构,破坏细胞膜的完整性,并同时介导细胞向外界释放大量促炎细胞因子和危险信号。Gasdermin家族蛋白介导的细胞焦亡与促炎因子释放在感染、炎症相关疾病以及肿瘤中发挥了重要作用。综述介绍了gasdermin家族蛋白的激活与成孔机制,以及gasdermins在感染性疾病、炎症相关疾病与肿瘤中的作用,总结并展望了gasdermin家族蛋白作为多种疾病治疗靶标的潜力。

Pyroptosis,a programmed inflammatory cell death,is executed by gasdermin family members.In response to danger signals,gasdermin is subjected to protease-mediated cleavage and activation,releasing its N-terminal domain with membrane pore-forming activity.N-terminal gasdermin binds to cell membrane phospholipids,and oligomerizes and forms stable membrane pore structures,causing loss of membrane integrity and secretion of pro-inflammatory cytokines and alarmins.Gasdermin-mediated pyroptosis and inflammatory responses play key roles in multiple biological processes including infection,inflammatory diseases as well as cancers.This review introduces the activation and pore-forming mechanisms of gasdermin family members and their roles in the above-mentioned diseases,and also highlights the therapeutic potentials in the treatment of related diseases by targeting gasdermins.