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

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. and Schroder, Kate (2018) Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. The Journal of Experimental Medicine, 215 3: 827-840. doi:10.1084/jem.20172222

Author 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
Title Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
Journal name The Journal of Experimental Medicine   Check publisher's open access policy
ISSN 1540-9538
Publication date 2018-02-06
Year available 2016
Sub-type Article (original research)
DOI 10.1084/jem.20172222
Open Access Status Not yet assessed
Volume 215
Issue 3
Start page 827
End page 840
Total pages 14
Place of publication New York, NY United States
Publisher Rockefeller University Press
Language eng
Subject 2723 Immunology and Allergy
2403 Immunology
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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1059729
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Created: Wed, 14 Feb 2018, 11:01:37 EST