Activity of caspase-8 determines plasticity between cell death pathways.

Area of Science:

• Cellular Biology
• Immunology
• Molecular Biology

Background:

• Caspase-8 has dual roles, mediating apoptosis and suppressing necroptosis.
• Mice lacking functional caspase-8 exhibit embryonic lethality, suggesting a pro-death scaffolding function.

Purpose of the Study:

• To investigate the pro-death scaffolding function of inactive caspase-8.
• To elucidate the molecular mechanisms underlying the lethality observed in mice with inhibited caspase-8 and MLKL.

Main Methods:

• Utilized genetically modified mouse models (Casp8(C362A), Mlkl-/-, Casp1-/-, Asc-/-, Casp11-/-).
• Analyzed caspase-1-dependent cleavage of GSDMD and downstream caspases.
• Examined ASC speck formation and caspase-11 upregulation in intestinal tissues.

Main Results:

• Inactive caspase-8 (CASP8(C362A)) induced ASC speck formation and caspase-1-dependent cleavage of GSDMD, caspase-3, and caspase-7 in MLKL-deficient mice.
• Caspase-1 and ASC were critical for the perinatal lethal phenotype.
• Upregulation of caspase-11 also contributed to lethality.
• A necroptosis-independent function of RIPK3 also contributed to lethality.

Conclusions:

• Inactive caspase-8 possesses a pro-death scaffolding function that activates inflammatory caspases (caspase-1 and caspase-11).
• This pathway involves ASC speck formation and GSDMD cleavage, leading to perinatal lethality.
• The study reveals significant plasticity in cell death pathways, with implications for understanding inflammatory diseases.