The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11
Yingchao Hu, Yuying Jiang, Sheng Li, Xiaoqing Ma, Min Chen, Rui Yang, Shuang Wen, Paul N. Moynagh, Bingwei Wang, Gang Hu, Shuo Yang
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.