Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis

• Published in: Cell reports (Cambridge) Vol. 43; no. 9; p. 114728
• Main Authors: Li, Xinran, Li, Xiao, Xiang, Cong, Cao, Jin, Guo, Jiansheng, Zhu, Shilei, Tan, Jingyi, Wang, Lijing, Gao, Chun, Liu, Shengduo, Zhao, Lifeng, Yuan, Bo, Xu, Pinglong, Yang, Bing, Li, Dali, Zhao, Bin, Feng, Xin-Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2024; Elsevier
• Subjects: CP: Immunology; CP: Metabolism; gastric cancer; GSDMA; phosphorylation; pyroptotic cell death; skin inflammation; starvation; ULK1; starvation; CP: Immunology; pyroptotic cell death; GSDMA; gastric cancer; CP: Metabolism; ULK1; phosphorylation; skin inflammation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114728

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. [Display omitted] •GSDMA is activated to induce pyroptosis upon severe starvation•Dual depletion of amino acids and ATP enables ULK1 to phosphorylate GSDMA•GSDMA suppresses gastric tumor malignancy in mouse orthotopic tumor models•Phospho-mimetic activation of GSDMA mediates skin inflammation Li et al. find that, under conditions of severe starvation, GSDMA is activated via phosphorylation and mediates pyroptosis. Data from animal models suggest that GSDMA-mediated cell death is immunogenic and may help suppress tumor malignancy.