2. Academic Validation
  3. Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis

Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis

  • Cell Rep. 2024 Sep 24;43(9):114728. doi: 10.1016/j.celrep.2024.114728.
Xinran Li 1,  Xiao Li 2,  Cong Xiang 2,  Jin Cao 3,  Jiansheng Guo 4,  Shilei Zhu 3,  Jingyi Tan 2,  Lijing Wang 2,  Chun Gao 2,  Shengduo Liu 2,  Lifeng Zhao 5,  Bo Yuan 3,  Pinglong Xu 6,  Bing Yang 2,  Dali Li 7,  Bin Zhao 3,  Xin-Hua Feng 8
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 4 Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 5 ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, Zhejiang 311200, China.
  • 6 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; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 7 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 8 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; Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang 321000, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China; The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310009, China. Electronic address: fenglab@zju.edu.cn.
PMID: 39264808 DOI: 10.1016/j.celrep.2024.114728
Abstract

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.

Keywords

CP: Immunology; CP: Metabolism; GSDMA; ULK1; gastric cancer; phosphorylation; pyroptotic cell death; skin inflammation; starvation.

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