Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China.
Institute of Brain Sciences, Nanjing University, Nanjing, China.
Front Immunol. 2022 Jun 14;13:893912. doi: 10.3389/fimmu.2022.893912. eCollection 2022.
Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1β, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.
Gasdermin D (GSDMD) 作为一种关键的执行者，可引发细胞焦亡，并且作为宿主防御、炎症、自身免疫性疾病和许多其他全身性疾病中的一个有吸引力的检查点而出现。虽然经典的和非经典的炎性小体介导的经典 GSDMD 切割、GSDMD-NT 向细胞膜的迁移、GSDMD-NT 寡聚化和孔形成已经得到很好的认识，但 GSDMD 在特定条件下超出其经典功能的一些独特特征，包括 GSDMD 的非溶细胞功能，GSDMD 信号的修饰和调节机制也引起了极大的关注，并在生物学过程和疾病中发挥了关键作用。在本综述中，我们强调了细胞焦亡过程中 GSDMD 蛋白的表达、稳定、修饰、激活、孔形成和修复，特别是 GSDMD 信号的调节和修饰，如 GSDMD 多泛素化复合物和 IL-1β的非细胞焦亡释放、ADP-核糖基化、NINJ1 在孔形成中的作用、GSDMD 结合蛋白 TRIM21、GSDMD 琥珀酰化以及 Rag-mTOR-ROS 对 GSDMD 的调控。我们还讨论了针对 GSDMD 的新型治疗策略，并总结了最近发现的具有广阔前景的抑制剂。
