PDF(Pubmed)
Abstract：
When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. Determination of the propensity of various gasdermin family members to cause pyroptosis has been handicapped by the fact that for many of them, the mechanisms and timing of their activation are uncertain. In this article, we exploit the recently discovered exosite-mediated recognition of gasdermin D (GSDMD) by the inflammatory caspases to develop a system that activates gasdermin family members in an efficient and equivalent manner. We leverage this system to show that upon activation, GSDMD and gasdermin A (GSDMA) exhibit differential subcellular localization, differential plasma membrane permeabilization, and differential lytic cell death. While GSDMD localizes rapidly to both the plasma membrane and organelle membranes, GSDMA preferentially localizes to the mitochondria with delayed and diminished accumulation at the plasma membrane. As a consequence of this differential kinetics of subcellular localization, N-terminal GSDMA results in early mitochondrial dysfunction relative to plasma membrane permeabilization. This study thus challenges the assumption that gasdermin family members effect cell death through identical mechanisms and establishes that their activation in their respective tissues of expression likely results in different immunological outcomes.
摘要：
激活时,gasdermin家族成员被认为是导致裂解细胞死亡的成孔蛋白。尽管如此,许多研究表明，裂解细胞死亡的阈值取决于哪个gasdermin家族成员被激活。确定各种gasdermin家族成员的倾向性导致焦度下降的事实是，对于他们中的许多人来说，其激活的机制和时间尚不确定。在这篇文章中,我们利用最近发现的exosite介导的炎性半胱天冬酶对gasderminD（GSDMD）的识别来开发一种以有效和等效的方式激活gasdermin家族成员的系统。我们利用这个系统来表明，一旦激活，GSDMD和GasderminA（GSDMA）表现出差异的亚细胞定位，差异质膜透化，和差异裂解细胞死亡。虽然GSDMD迅速定位在质膜和细胞器膜，GSDMA优先定位于线粒体，在质膜上的积累延迟和减少。由于亚细胞定位的这种差异动力学，相对于质膜透化,N-末端GSDMA导致早期线粒体功能障碍。因此，这项研究挑战了gasdermin家族成员通过相同机制影响细胞死亡的假设，并确立了它们在各自表达组织中的激活可能导致不同的免疫学结果。
