AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Inflammasomes act as sentinels in innate immunity, detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPs) to induce cell death.
• During infection, pathogens can trigger multiple PAMPs/DAMPs, simultaneously engaging various inflammasome sensors.
• Understanding the interplay between inflammasome sensors is crucial for deciphering innate immune responses.

Purpose of the Study:

• To investigate the regulatory role of AIM2 in innate immune signaling and inflammatory cell death.
• To identify the molecular complex driving PANoptosis.
• To elucidate the interaction between AIM2, pyrin, and ZBP1 in host defense.

Main Methods:

• Investigated the function of AIM2, pyrin, and ZBP1 in host protection during infections with herpes simplex virus 1 and Francisella novicida.
• Analyzed the composition of the multi-protein complex driving inflammatory cell death (PANoptosis).
• Characterized the AIM2-mediated multi-protein complex, termed the AIM2 PANoptosome.

Main Results:

• AIM2 was found to regulate pyrin and ZBP1, promoting inflammatory signaling and PANoptosis.
• AIM2, pyrin, and ZBP1 were identified as components of a large multi-protein complex driving PANoptosis.
• This complex includes ASC, caspase-1, caspase-8, RIPK3, RIPK1, and FADD.

Conclusions:

• A novel regulatory and molecular interaction between AIM2, pyrin, and ZBP1 was defined.
• The AIM2 PANoptosome, a multi-protein complex, drives PANoptosis and provides host protection.
• Findings offer insights into innate immunity and inflammatory cell death, suggesting therapeutic targets for related diseases.