2. Academic Validation
  3. The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11

The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11

  • Proc Natl Acad Sci U S A. 2022 Nov 8;119(45):e2210809119. doi: 10.1073/pnas.2210809119.
Yingchao Hu 1,  Yuying Jiang 1,  Sheng Li 1 2,  Xiaoqing Ma 3,  Min Chen 1,  Rui Yang 1,  Shuang Wen 1,  Paul N Moynagh 4 5,  Bingwei Wang 3,  Gang Hu 3,  Shuo Yang 1
Affiliations

Affiliations

  • 1 Department of Immunology, Key Laboratory of Immunological Environment and Disease, Gusu School, State Key Laboratory of Reproductive Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, Nanjing Medical University, 211166 Nanjing, China.
  • 2 Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, 200092 Shanghai, China.
  • 3 Department of Pharmacology, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
  • 4 Kathleen Lonsdale Institute for Human Health Research, Department of Biology, National University of Ireland Maynooth, Maynooth W23 X021, Ireland.
  • 5 Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT7 1NN, United Kingdom.
PMID: 36322773 DOI: 10.1073/pnas.2210809119
Abstract

Inflammatory pathways usually utilize negative feedback regulatory systems to prevent tissue damage arising from excessive inflammatory response. Whether such negative feedback mechanisms exist in inflammasome activation remains unknown. Gasdermin D (GSDMD) is the Pyroptosis executioner of downstream inflammasome signaling. Here, we found that GSDMD, after its cleavage by Caspase-1/11, utilizes its RFWK motif in the N-terminal β1-β2 loop to inhibit the activation of Caspase-1/11 and downstream inflammation in a negative feedback manner. Furthermore, an RFWK motif-based peptide inhibitor can inhibit Caspase-1/11 activation and its downstream substrates GSDMD and interleukin-1β cleavage, as well as lipopolysaccharide-induced sepsis in mice. Collectively, these findings provide a demonstration of the N-terminal fragment of GSDMD as a negative feedback regulator controlling inflammasome activation and a detailed delineation of the underlying inhibitory mechanism.

Keywords

Gasdermin D; antiinflammation; inflammasome.

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