1. The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11.
- Author
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Hu Y, Jiang Y, Li S, Ma X, Chen M, Yang R, Wen S, Moynagh PN, Wang B, Hu G, and Yang S
- Subjects
- Animals, Mice, Caspase 1 metabolism, Feedback, Neoplasm Proteins metabolism, Phosphate-Binding Proteins, Pore Forming Cytotoxic Proteins pharmacology, Inflammasomes metabolism, Intracellular Signaling Peptides and Proteins metabolism
- 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.
- Published
- 2022
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