Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity

• Published in: The Journal of experimental medicine Vol. 215; no. 3; pp. 827 - 840
• Main Authors: Boucher, Dave, Monteleone, Mercedes, Coll, Rebecca C, Chen, Kaiwen W, Ross, Connie M, Teo, Jessica L, Gomez, Guillermo A, Holley, Caroline L, Bierschenk, Damien, Stacey, Katryn J, Yap, Alpha S, Bezbradica, Jelena S, Schroder, Kate
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.03.2018
• Subjects: Caspase; Caspase-1; Cell size; Deactivation; Dimerization; Dimers; Dominant species; Inflammasomes; Inflammation; Kinetics; Protease; Proteases; Proteinase; Shutdowns; Signaling
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20172222

Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome-caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.