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

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• Caspase-1 (CASP1) is primarily known for interleukin-1 beta (IL-1β) processing and pyroptosis.
• The specific role of CASP1 in leukemia pathogenesis remained largely undefined prior to this study.

Purpose of the Study:

• To elucidate the function of Caspase-1 (CASP1) in leukemia.
• To investigate the molecular mechanisms underlying CASP1's role in leukemic cells.
• To explore CASP1 as a potential therapeutic target in leukemia.

Main Methods:

• Utilized genetic deletion of CASP1 and disruption of its CARD domain in leukemia models.
• Investigated the impact on leukemic cell growth, differentiation, and in vivo tumor burden.
• Developed and tested a proteolysis-targeting chimera (PROTAC) degrader for Pro-CASP1.

Main Results:

• Loss of CASP1 impaired leukemic cell growth, promoted differentiation, and reduced leukemic burden.
• CASP1's scaffolding function, independent of protease activity, was critical for its effects.
• CASP1 interacts with RPTOR (mTORC1 component) to regulate nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling.

Conclusions:

• Caspase-1 (CASP1) acts as a crucial scaffolding hub regulating mTORC1-NF-κB signaling in leukemia.
• CASP1's scaffolding activity, not its enzymatic function, is key to its role in leukemia.
• Targeting CASP1, particularly its scaffolding function, represents a novel therapeutic vulnerability in leukemia treatment.