The Inflammasome Lab have uncovered precisely how caspase-1 is activated upon inflammasomes, which has revealed a new model for inflammasome signalling, function, and signal shutdown. This discovery is now published in the Journal of Experimental Medicine.
Boucher D, Monteleone M1, Coll RC1, Chen KW1, Ross CM, Teo JL, Gomez GA, Holley CL, Bierschenk D, Stacey KJ, Yap AS, Bezbradica JS and Schroder K. (2018).
Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. Journal of Experimental Medicine In press. Pubmed
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Defusing inflammasomes. Sandstrom A, Vance RE. Journal of Experimental Medicine. Pubmed
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.
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