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

TY - JOUR

T1 - Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity

AU - Boucher, Dave

AU - Monteleone, Mercedes

AU - Coll, Rebecca C

AU - Chen, Kaiwen W

AU - Ross, Connie M

AU - Teo, Jessica L

AU - Gomez, Guillermo A

AU - Holley, Caroline L

AU - Bierschenk, Damien

AU - Stacey, Katryn J

AU - Yap, Alpha S

AU - Bezbradica, Jelena S

AU - Schroder, Kate

N1 - © 2018 Boucher et al.

PY - 2018/2/6

Y1 - 2018/2/6

N2 - 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.

AB - 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.

KW - Animals

KW - Caspase 1/metabolism

KW - Inflammasomes/metabolism

KW - Kinetics

KW - Macrophages/drug effects

KW - Mice, Inbred C57BL

KW - Models, Biological

KW - Nigericin/pharmacology

KW - Protein Multimerization

U2 - 10.1084/jem.20172222

DO - 10.1084/jem.20172222

M3 - Article

C2 - 29432122

SN - 0022-1007

VL - 215

SP - 827

EP - 840

JO - The Journal of experimental medicine

JF - The Journal of experimental medicine

IS - 3

ER -