MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China; ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, Zhejiang 311200, China; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Cell Rep. 2024 Sep 24;43(9):114728. doi: 10.1016/j.celrep.2024.114728. Epub 2024 Sep 10.
Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B-E (GSDMB-GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.
细胞焦亡是一种促炎形式的程序性细胞死亡，对于宿主防御病原体和危险信号至关重要。Gasdermin 蛋白 B-E（GSDMB-GSDME）的蛋白水解切割被认为是细胞焦亡的触发因素，但 GSDMA 的细胞内激活机制仍不清楚。在这里，我们证明严重饥饿通过 GSDMA 的磷酸化诱导激活诱导细胞焦亡。营养应激通过 Unc-51 样自噬激活激酶 1（ULK1）介导的磷酸化刺激 GSDMA 的激活。ULK1 或 GSDMA 的磷酸模拟 Ser353Asp 突变体对人 GSDMA 的 Ser353 磷酸化将 GSDMA 从自身抑制中释放出来，促进其膜靶向和细胞焦亡的起始。为了进一步验证 GSDMA 磷酸化的重要性，我们生成了小鼠 Gsdma 的组成性激活突变体 Ser354Asp，该突变体诱导小鼠皮肤炎症和增生，类似于激活的 Gsdma 的表型。这项研究揭示了 GSDMA 的磷酸化作为细胞焦亡起始和细胞对营养应激反应的机制。
