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

Dave Boucher, Mercedes Monteleone, Rebecca C Coll, Kaiwen W Chen, Connie M Ross, Jessica L Teo, Guillermo A Gomez, Caroline L Holley, Damien Bierschenk, Katryn J Stacey, Alpha S Yap, Jelena S Bezbradica, Kate Schroder

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)827-840
Number of pages14
JournalThe Journal of experimental medicine
Issue number3
Publication statusPublished - 6 Feb 2018

Bibliographical note

© 2018 Boucher et al.


  • Animals
  • Caspase 1/metabolism
  • Inflammasomes/metabolism
  • Kinetics
  • Macrophages/drug effects
  • Mice, Inbred C57BL
  • Models, Biological
  • Nigericin/pharmacology
  • Protein Multimerization

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