Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion PMID: 35794369

ADC Targets in Oncology

2026-04-10

Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion

Nat Immunol. 2022 Jul;23(7):1021-1030. doi: 10.1038/s41590-022-01255-6.

Wen Chen ^# ¹ ² , Shuangfeng Chen ^# ¹ ³ , Chenghua Yan ^# ¹ , Yaguang Zhang ^# ⁴ , Ronghua Zhang ^# ¹ , Min Chen ^# ⁵ , Shufen Zhong ¹ , Weiguo Fan ¹ , Songling Zhu ¹ , Danyan Zhang ¹ ³ , Xiao Lu ¹ , Jia Zhang ¹ , Yuying Huang ¹ , Lin Zhu ¹ , Xuezhen Li ¹ , Dawei Lv ² , Yadong Fu ¹ , Houkun Iv ¹ ³ , Zhiyang Ling ¹ , Liyan Ma ¹ , Hai Jiang ¹ , Gang Long ² , Jinfang Zhu ⁶ , Dong Wu ⁷ , Bin Wu ⁸ , Bing Sun ⁹ ¹⁰

Affiliations

1. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
2. Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences University, Shanghai, China.
3. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
4. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
5. Department of Respiratory and Critical Care Medicine, Affiliated Hospital, Institute of Respiratory Diseases, Guangdong Medical College, Zhanjiang, China.
6. Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
7. Department of Respiratory and Critical Care Medicine, Affiliated Hospital, Institute of Respiratory Diseases, Guangdong Medical College, Zhanjiang, China. [email protected].
8. Department of Respiratory and Critical Care Medicine, Affiliated Hospital, Institute of Respiratory Diseases, Guangdong Medical College, Zhanjiang, China. [email protected].
9. State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
10. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory Caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.