Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis

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  • 作者：Xinran Li, Xiao Li, Cong Xiang, Jin Cao, Jiansheng Guo, Shilei Zhu, Jingyi Tan, Lijing Wang, Chun Gao, Shengduo Liu, Lifeng Zhao, Bo Yuan, Pinglong Xu, Bing Yang, Dali Li, Bin Zhao, Xin-Hua Feng
  • 期刊：Cell Reports
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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.

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