Chen Shouwen, Gong Yuxin, Li Shuxin, Yang Dahai, Zhang Yuanxing, Liu Qin
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.
Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, 519000, China; Shanghai Engineering Research Center of Marine Cultured Animal Vaccines, Shanghai, 200237, China.
Dev Comp Immunol. 2023 Dec;149:104904. doi: 10.1016/j.dci.2023.104904. Epub 2023 Aug 3.
Pyroptosis, an inflammatory form of programmed cell death, is directly executed by gasdermin (GSDM) depending on its N-terminal pore-forming fragment-mediated membrane-disrupting, triggering intracellular contents release, which plays important roles in mammalian anti-infection and anti-tumor immune responses. However, whether pyroptosis engages in the regulation of tissue regeneration remains largely unknown. Here, utilizing Hydra vulgaris as the research model, we found that an HyCARD2-HyGSDME-mediated pyroptosis signalling is activated in both head and foot regenerated tips after amputation. Impeding pyroptosis by knocking down the expression of either HyGSDME or HyCARD2 significantly hampered both head and foot regeneration in Hydra. Mechanistically, the activation of HyCARD2-HyGSDME axis at wound sites is dependent of intracellular mitochondrial reactive oxygen species (mtROS), the removing of which hindered Hydra head regeneration. Moreover, the HyCARD2-HyGSDME axis-gated pyroptosis was found to enhance the initial secretion and upregulated expression of Wnt3. Collectively, these findings indicate that gasdermin-gated pyroptosis is critical for the evoking of Wnt signalling to facilitate Hydra tissue regeneration, which provides insights into functional diversification within the gasdermin family in the animal kingdom.
细胞焦亡是一种程序性细胞死亡的炎症形式，由gasdermin（GSDM）直接执行，这取决于其N端成孔片段介导的膜破坏，触发细胞内内容物释放，在哺乳动物抗感染和抗肿瘤免疫反应中起重要作用。然而，细胞焦亡是否参与组织再生的调节在很大程度上仍然未知。在这里，利用普通水螅作为研究模型，我们发现在截肢后的头部和足部再生顶端，一种由HyCARD2-HyGSDME介导的细胞焦亡信号被激活。通过敲低HyGSDME或HyCARD2的表达来抑制细胞焦亡，显著阻碍了水螅的头部和足部再生。从机制上讲，伤口部位HyCARD2-HyGSDME轴的激活依赖于细胞内线粒体活性氧（mtROS），去除mtROS会阻碍水螅头部再生。此外，发现HyCARD2-HyGSDME轴门控的细胞焦亡增强了Wnt3的初始分泌和上调表达。总的来说，这些发现表明gasdermin门控的细胞焦亡对于激活Wnt信号以促进水螅组织再生至关重要，这为动物王国中gasdermin家族的功能多样化提供了见解。
