Caspase-1 initiates apoptosis in the absence of gasdermin D

Area of Science:

• Cellular biology
• Immunology
• Molecular mechanisms of cell death

Background:

• Inflammasome activation by caspase-1 typically induces pyroptosis, a programmed necrosis mediated by gasdermin D (GSDMD).
• GSDMD-deficient cells exhibit caspase-1-mediated cell death, suggesting alternative pathways exist.
• Understanding these alternative pathways is crucial for comprehending inflammatory responses and cell death.

Purpose of the Study:

• To elucidate the molecular mechanisms of caspase-1-initiated cell death in GSDMD-deficient or low-expressing cells.
• To investigate the role of caspase-1 in inducing apoptosis independent of canonical pyroptosis.
• To explore the biological significance of caspase-1-induced apoptosis in specific cell types.

Main Methods:

• Utilizing GSDMD-deficient cell models and inflammasome stimulation.
• Employing chemical dimerization of caspase-1 to trigger cell death.
• Investigating apoptotic pathways, including the Bid-caspase-9-caspase-3 axis and GSDME involvement.
• Assessing cell death in primary cells like cortical neurons and mast cells with low GSDMD expression.

Main Results:

• Inflammasome activation in GSDMD-deficient macrophages induces caspase-1-dependent apoptosis, involving caspase-3 activation.
• Caspase-1-induced apoptosis in GSDMD-deficient cells proceeds through the Bid-caspase-9-caspase-3 pathway.
• GSDME-dependent secondary necrosis/pyroptosis can follow caspase-1-induced apoptosis.
• Cortical neurons and mast cells undergo caspase-1- and Bid-dependent apoptosis under specific stimuli, despite low GSDMD expression.

Conclusions:

• Caspase-1 can induce apoptosis in GSDMD-low/null cells through a distinct molecular mechanism.
• The Bid-caspase-9-caspase-3 axis is a key component of this alternative caspase-1-mediated cell death.
• Caspase-1-induced apoptosis plays a significant role in cell types with limited GSDMD expression, expanding the understanding of programmed cell death.