Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia

Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.

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Publication Details

Journal
Cell chemical biology
Published
2026-01-01
DOI
https://doi.org/10.1016/j.chembiol.2025.12.002
Citations
2
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
44.47
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article

Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia

John C. Fisher, John T. Cunningham, Issac Choi, Kenneth D. Greis et al.
2 citations
Cell chemical biology
Protein Degradation and Inhibitors
44.47
article

Scaffolding-dependent CASP1 constrains excessive cell-intrinsic inflammatory signaling in leukemia

John C. Fisher, John T. Cunningham, Issac Choi, Kenneth D. Greis, Courtnee Clough, Annabelle Anandappa, Kathleen Hueneman, Daniel T. Starczynowski, Timothy M. Chlon, William Seibel, Aishlin Hassan, Eric Vick, Emma Uible, Lynn Lee, Jorge Henao‐Mejia, Andrew Volk, C. D. Jones, Bibek Karki, Kwangmin Choi, Chandrashekhar Pasare
article en
2 citations

Abstract

Caspase-1 (CASP1) is best known for regulating IL-1β processing and pyroptosis; however, its role in leukemia has not been clearly defined. Here, we show that loss of CASP1 impairs leukemic cell growth, drives differentiation, and reduces leukemic burden in vivo, independent of its CASP1 protease activity. Instead, CASP1 functions as a scaffolding hub, controlling nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling via its interaction with raptor (RPTOR), a component of mTORC1. Deletion of CASP1 or disruption of its CARD domain induces excessive NF-κB activity and impairs leukemic cell function. We further developed a proteolysis-targeting chimera (PROTAC) degrader that selectively depletes Pro-CASP1 and suppresses leukemic cells. These findings reveal CASP1 as a regulator of mTORC1-NF-κB signaling in leukemia and highlight its scaffolding activity as a therapeutic vulnerability.

Cell chemical biologyVol. 33(1)
Cincinnati Children's Hospital Medical Center (US), Children's Hospital of Philadelphia (US), University of Cincinnati (US), University of Pennsylvania (US), University of Cincinnati Medical Center (US)
Openalex Percentile: Top 0%
Protein Degradation and Inhibitors
44.47
DOIOpen Access PDFOpenAlex
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