TNFAIP3-interacting protein 1 (ABIN-1) negatively regulates caspase-8/FADD-dependent pyroptosis

Area of Science:

• Cell Biology
• Immunology
• Molecular Biology

Background:

• TNFAIP3-interacting protein 1 (TNIP1/ABIN-1) is a ubiquitin-binding protein known to inhibit apoptosis and necroptosis.
• The role of ABIN-1 in regulating pyroptosis, another form of programmed cell death, remained largely unexplored.

Purpose of the Study:

• To investigate the function of ABIN-1 in pyroptosis regulation.
• To elucidate the molecular mechanisms underlying ABIN-1's role in programmed cell death pathways.

Main Methods:

• Utilized mouse embryonic fibroblasts and macrophages deficient in ABIN-1.
• Employed poly(I:C) + TAK1 inhibitor 5Z-7-oxozeaenol to induce cell death.
• Investigated pyroptosis, apoptosis, and necroptosis using genetic deletion models in mice and analyzed caspase-8 and gasdermin involvement.

Main Results:

• ABIN-1 deficiency sensitized cells and mice to pyroptosis, apoptosis, and necroptosis, worsening sepsis outcomes.
• ABIN-1 deficiency induced gasdermin-E-mediated pyroptosis in fibroblasts and gasdermin-D-mediated pyroptosis in macrophages, both dependent on caspase-8.
• ABIN-1 deficiency facilitated FAS-associated death domain protein recruitment to caspase-8, revealing a conserved inhibitory mechanism.

Conclusions:

• ABIN-1 acts as a negative regulator of pyroptosis, in addition to its known roles in apoptosis and necroptosis.
• ABIN-1's suppression of multiple programmed cell death pathways suggests its potential as a therapeutic target for inflammatory disorders.