Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

Area of Science:

• Cellular Biology
• Immunology
• Pathology

Background:

• Caspase-4 senses cytosolic bacterial lipopolysaccharide (LPS) and triggers pyroptosis.
• Mechanisms of caspase-4 activation by host-derived factors remain unclear.

Purpose of the Study:

• To investigate how caspase-4 is activated by host-derived factors.
• To elucidate the role of mitochondrial permeability transition (MPT) in caspase-4 activation and pyroptosis.

Main Methods:

• Induction of MPT using bile acids, calcium overload, or ANT1 activator.
• Analysis of protein complex assembly (Apaf-1 pyroptosome) involving Apaf-1 and caspase-4.
• Assessment of caspase-4's downstream cleavage targets, including caspase-3, GSDME, and GSDMD.

Main Results:

• MPT triggers the assembly of the Apaf-1 pyroptosome (7:2 ratio of Apaf-1 to caspase-4).
• Activated caspase-4 in the Apaf-1 pyroptosome cleaves caspase-3, leading to GSDME-mediated pyroptosis.
• Caspase-4-initiated, GSDME-executed pyroptosis is implicated in cholestatic liver failure.

Conclusions:

• The Apaf-1 pyroptosome is a key machinery for sensing MPT signals and executing pyroptosis.
• This pathway explains intrinsic pyroptosis under sterile conditions.
• Findings provide insights into cholestatic liver failure mechanisms.