DNA-triggered AIM2 condensation orchestrates immune activation and regulation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• The Absent in Melanoma 2 (AIM2) protein is a key sensor of cytosolic DNA, initiating innate immune responses.
• AIM2 activation is critical for inflammasome assembly and subsequent inflammatory signaling, but its precise mechanism remains unclear.

Purpose of the Study:

• To elucidate the activation mechanism of the AIM2 inflammasome sensor.
• To investigate the role of liquid-liquid phase separation in AIM2 function and immune complex assembly.

Main Methods:

• In vitro and cellular assays to observe AIM2 behavior upon DNA binding.
• Direct structural determination of protein assemblies within condensates.
• Analysis of mutant AIM2 proteins to assess the impact on condensation and immune function.

Main Results:

• AIM2 undergoes liquid-liquid phase separation upon binding to cytosolic DNA, forming dynamic condensates.
• These AIM2 condensates act as platforms for inflammasome and PANoptosome assembly, facilitating immune activation.
• Structural analysis revealed the formation of active ASC filaments within these condensates.
• Disruption of AIM2 condensation impaired immune complex assembly, cell death, antimicrobial defense, and intestinal homeostasis.

Conclusions:

• Liquid-phase condensation is a fundamental mechanism governing AIM2 activation and function.
• AIM2 condensates serve as regulatory hubs influencing immune homeostasis and pathogen evasion.
• Targeting AIM2 condensation presents a potential therapeutic strategy for immune-related diseases.