State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai 200237, China.
Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China.
Sci Adv. 2023 Jul 21;9(29):eadh4054. doi: 10.1126/sciadv.adh4054.
Inflammatory caspases sensing lipopolysaccharide (LPS) to drive gasdermin (GSDM)-mediated pyroptosis is an important immune response mechanism for anti-infection defense in mammals. In this work, we resolved an LPS-induced and GSDM-gated pyroptosis signaling cascade in Cnidarians. Initially, we identified a functional GSDM protein, HyGSDME, in , executing cytosolic LPS-induced pyroptosis in a caspase-dependent manner. Further, we identified a proinflammatory caspase, HyCaspA capable of sensing cytosolic LPS by an uncharacterized N-terminal domain relying on its unique hydrophobic property, thereby triggering its oligomerization and self-activation. Subsequently, the LPS-activated HyCaspA cleaved an apoptotic caspase, HyCARD2, to trigger HyGSDME-gated pyroptosis. Last, HyGSDME exhibited an enriched distribution on the ectodermal layer of polyps, exerting a canonical immune defense function against surface-invading bacteria. Collectively, our work resolved an ancient pyroptosis signaling cascade in , suggesting that inflammatory caspases sensing cytosolic LPS to initiate GSDM-gated pyroptosis are a conserved immune defense mechanism from Cnidarians to mammals.
炎症小体感应脂多糖 (LPS) 以驱动 GSDM 介导的细胞焦亡是哺乳动物抗感染防御的重要免疫反应机制。在这项工作中，我们解析了刺胞动物中 LPS 诱导和 GSDM 门控细胞焦亡信号级联。首先，我们在 中鉴定了一种功能性 GSDM 蛋白 HyGSDME，它以依赖半胱天冬酶的方式执行细胞质 LPS 诱导的细胞焦亡。此外，我们发现一种炎症小体 caspase HyCaspA 能够通过其独特的疏水性特性感应细胞质 LPS，从而触发其寡聚化和自身激活。随后，LPS 激活的 HyCaspA 切割凋亡半胱天冬酶 HyCARD2，触发 HyGSDME 门控的细胞焦亡。最后，HyGSDME 在 息肉的外胚层上表现出丰富的分布，对入侵体表的细菌发挥典型的免疫防御功能。总的来说，我们的工作解析了 中的古老细胞焦亡信号级联，表明炎症小体感应细胞质 LPS 以启动 GSDM 门控的细胞焦亡是从刺胞动物到哺乳动物的保守免疫防御机制。
