Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome

Area of Science:

• Innate immunity
• Molecular and cell biology
• Host-pathogen interactions

Background:

• Caspase-11 is a key cytosolic sensor and protease involved in innate immunity against Gram-negative bacteria.
• Its activation by lipopolysaccharide (LPS) leads to inflammasome assembly, gasdermin D cleavage, and cell death, but the protease activation mechanism is unclear.
• Dysregulated caspase-11 activity contributes to endotoxic shock.

Purpose of the Study:

• To elucidate the molecular mechanism of caspase-11 protease activation.
• To define the role of self-cleavage in caspase-11 function.
• To understand how caspase-11 drives inflammatory responses and host defense.

Main Methods:

• Investigated caspase-11 dimerization and auto-cleavage.
• Analyzed self-cleavage at the D285 site within the caspase-11 linker region.
• Assessed the role of D285 self-cleavage in gasdermin D cleavage, cell death, and IL-1β production.

Main Results:

• Caspase-11 dimerization is necessary and sufficient for basal protease function, including auto-cleavage.
• Self-cleavage at D285 is essential for generating the fully active caspase-11 protease (p32/p10).
• Active caspase-11 mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production.

Conclusions:

• LPS-induced non-canonical inflammasome signaling triggers caspase-11 self-cleavage at D285.
• This self-cleavage generates the active protease required for downstream inflammatory effectors and host defense.
• The study provides a detailed molecular mechanism for LPS-induced inflammation and cell death mediated by caspase-11.