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

Authors
  • Boucher, Dave1
  • Monteleone, Mercedes1
  • Coll, Rebecca C1
  • Chen, Kaiwen W1
  • Ross, Connie M1
  • Teo, Jessica L1
  • Gomez, Guillermo A1, 2
  • Holley, Caroline L1
  • Bierschenk, Damien1
  • Stacey, Katryn J3
  • Yap, Alpha S1
  • Bezbradica, Jelena S1, 4
  • Schroder, Kate5
  • 1 Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia. , (Australia)
  • 2 Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia. , (Australia)
  • 3 School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia. , (Australia)
  • 4 The Kennedy Institute of Rheumatology, University of Oxford, Oxford, England, UK.
  • 5 Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia [email protected] , (Australia)
Type
Published Article
Journal
Journal of Experimental Medicine
Publisher
The Rockefeller University Press
Publication Date
Feb 06, 2018
Identifiers
DOI: 10.1084/jem.20172222
PMID: 29432122
Source
Medline
License
Unknown

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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