Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
Date
2018
Authors
Boucher, D.
Monteleone, M.
Coll, R.C.
Chen, K.W.
Ross, C.M.
Teo, J.L.
Gomez, G.A.
Holley, C.L.
Bierschenk, D.
Stacey, K.J.
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Journal article
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Journal of Experimental Medicine (JEM), 2018; 215(3):827-840
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Abstract
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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Copyright 2018 Boucher et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license (https://creativecommons.org/licenses/by-nc-sa/4.0/)
Access Condition Notes: Published version available after 28 September 2018