Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
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 stud...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Rockefeller University Press
2018
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| _version_ | 1797071270469173248 |
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| author | Boucher, D Monteleone, M Coll, R Chen, K Ross, C Teo, J Gomez, G Holley, C Bierschenk, D Stacey, K Yap, A Bezbradica, J Schroder, K |
| author_facet | Boucher, D Monteleone, M Coll, R Chen, K Ross, C Teo, J Gomez, G Holley, C Bierschenk, D Stacey, K Yap, A Bezbradica, J Schroder, K |
| author_sort | Boucher, D |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:50:52Z |
| format | Journal article |
| id | oxford-uuid:5eba43a4-64d8-4db6-9844-f0ccdd8b976a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:50:52Z |
| publishDate | 2018 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | oxford-uuid:5eba43a4-64d8-4db6-9844-f0ccdd8b976a2022-03-26T17:42:32ZCaspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5eba43a4-64d8-4db6-9844-f0ccdd8b976aEnglishSymplectic Elements at OxfordRockefeller University Press2018Boucher, DMonteleone, MColl, RChen, KRoss, CTeo, JGomez, GHolley, CBierschenk, DStacey, KYap, ABezbradica, JSchroder, KHost-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. |
| spellingShingle | Boucher, D Monteleone, M Coll, R Chen, K Ross, C Teo, J Gomez, G Holley, C Bierschenk, D Stacey, K Yap, A Bezbradica, J Schroder, K Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title | Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title_full | Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title_fullStr | Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title_full_unstemmed | Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title_short | Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity |
| title_sort | caspase 1 self cleavage is an intrinsic mechanism to terminate inflammasome activity |
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