Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS
Inflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammasomes. Inflammasomes recruit caspases to undergo proximity-induced autoprocessing into an enzymatically active form th...
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eLife Sciences Publications Ltd
2024-01-01
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| Online Access: | https://elifesciences.org/articles/83725 |
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| author | Daniel C Akuma Kimberly A Wodzanowski Ronit Schwartz Wertman Patrick M Exconde Víctor R Vázquez Marrero Chukwuma E Odunze Daniel Grubaugh Sunny Shin Cornelius Taabazuing Igor E Brodsky |
| author_facet | Daniel C Akuma Kimberly A Wodzanowski Ronit Schwartz Wertman Patrick M Exconde Víctor R Vázquez Marrero Chukwuma E Odunze Daniel Grubaugh Sunny Shin Cornelius Taabazuing Igor E Brodsky |
| author_sort | Daniel C Akuma |
| collection | DOAJ |
| description | Inflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammasomes. Inflammasomes recruit caspases to undergo proximity-induced autoprocessing into an enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high-molecular-weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. However, the cellular correlates of Casp11 oligomerization and whether Casp11 forms an LPS-induced SMOC within cells remain unknown. Expression of fluorescently labeled Casp11 in macrophages revealed that cytosolic LPS induced Casp11 speck formation. Unexpectedly, catalytic activity and autoprocessing were required for Casp11 to form LPS-induced specks in macrophages. Furthermore, both catalytic activity and autoprocessing were required for Casp11 speck formation in an ectopic expression system, and processing of Casp11 via ectopically expressed TEV protease was sufficient to induce Casp11 speck formation. These data reveal a previously undescribed role for Casp11 catalytic activity and autoprocessing in noncanonical inflammasome assembly, and shed new light on the molecular requirements for noncanonical inflammasome assembly in response to cytosolic LPS. |
| first_indexed | 2024-03-08T13:23:45Z |
| format | Article |
| id | doaj.art-9a7de7c6836d438db9bfd14207873e03 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T13:23:45Z |
| publishDate | 2024-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-9a7de7c6836d438db9bfd14207873e032024-01-17T15:18:47ZengeLife Sciences Publications LtdeLife2050-084X2024-01-011310.7554/eLife.83725Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPSDaniel C Akuma0https://orcid.org/0000-0003-1079-6295Kimberly A Wodzanowski1https://orcid.org/0000-0001-8948-6788Ronit Schwartz Wertman2https://orcid.org/0000-0003-4297-3495Patrick M Exconde3Víctor R Vázquez Marrero4Chukwuma E Odunze5Daniel Grubaugh6Sunny Shin7https://orcid.org/0000-0001-5214-9577Cornelius Taabazuing8https://orcid.org/0000-0003-2361-5457Igor E Brodsky9https://orcid.org/0000-0001-7970-872XDepartment of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, United StatesDepartment of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDepartment of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDepartment of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesUniversity of Maryland, College Park, College Park, United StatesDepartment of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, United StatesDepartment of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDepartment of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, United StatesDepartment of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, United StatesInflammatory caspases are cysteine protease zymogens whose activation following infection or cellular damage occurs within supramolecular organizing centers (SMOCs) known as inflammasomes. Inflammasomes recruit caspases to undergo proximity-induced autoprocessing into an enzymatically active form that cleaves downstream targets. Binding of bacterial LPS to its cytosolic sensor, caspase-11 (Casp11), promotes Casp11 aggregation within a high-molecular-weight complex known as the noncanonical inflammasome, where it is activated to cleave gasdermin D and induce pyroptosis. However, the cellular correlates of Casp11 oligomerization and whether Casp11 forms an LPS-induced SMOC within cells remain unknown. Expression of fluorescently labeled Casp11 in macrophages revealed that cytosolic LPS induced Casp11 speck formation. Unexpectedly, catalytic activity and autoprocessing were required for Casp11 to form LPS-induced specks in macrophages. Furthermore, both catalytic activity and autoprocessing were required for Casp11 speck formation in an ectopic expression system, and processing of Casp11 via ectopically expressed TEV protease was sufficient to induce Casp11 speck formation. These data reveal a previously undescribed role for Casp11 catalytic activity and autoprocessing in noncanonical inflammasome assembly, and shed new light on the molecular requirements for noncanonical inflammasome assembly in response to cytosolic LPS.https://elifesciences.org/articles/83725noncanonical inflammasomecaspase-11LPSsepsiscaspase-1pyroptosis |
| spellingShingle | Daniel C Akuma Kimberly A Wodzanowski Ronit Schwartz Wertman Patrick M Exconde Víctor R Vázquez Marrero Chukwuma E Odunze Daniel Grubaugh Sunny Shin Cornelius Taabazuing Igor E Brodsky Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS eLife noncanonical inflammasome caspase-11 LPS sepsis caspase-1 pyroptosis |
| title | Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS |
| title_full | Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS |
| title_fullStr | Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS |
| title_full_unstemmed | Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS |
| title_short | Catalytic activity and autoprocessing of murine caspase-11 mediate noncanonical inflammasome assembly in response to cytosolic LPS |
| title_sort | catalytic activity and autoprocessing of murine caspase 11 mediate noncanonical inflammasome assembly in response to cytosolic lps |
| topic | noncanonical inflammasome caspase-11 LPS sepsis caspase-1 pyroptosis |
| url | https://elifesciences.org/articles/83725 |
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