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
  • 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: [email protected].
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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