| Zdroj: |
Hu, Y, Jiang, Y, Li, S, Ma, X, Chen, M, Yang, R, Wen, S, Moynagh, P N, Wang, B, Hu, G & Yang, S 2022, ' The Gasdermin D N-terminal fragment acts as a negative feedback system to inhibit inflammasome-mediated activation of Caspase-1/11 ', Proceedings of the National Academy of Sciences, vol. 119, no. 45, e2210809119 . https://doi.org/10.1073/pnas.2210809119 |
| Popis: |
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. |
