Signal-induced NLRP3 phase separation initiates inflammasome activation

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• The NLRP3 inflammasome (NLRP3) is a crucial immune sensor activated by diverse stimuli, but the precise sensing and activation mechanisms remain unclear.
• Understanding NLRP3 activation is vital for developing targeted therapies for inflammatory diseases.

Purpose of the Study:

• To elucidate the molecular mechanism underlying NLRP3 inflammasome activation by diverse stimuli.
• To identify key factors and processes involved in NLRP3 sensing and activation.

Main Methods:

• Investigated NLRP3 phase separation using cellular and in vitro assays.
• Analyzed the role of ZDHHC7-mediated palmitoylation and an intrinsically disordered region (IDR) in NLRP3 activation.
• Examined the effects of various NLRP3 agonists and amphiphilic molecules on NLRP3 phase separation and activation.

Main Results:

• NLRP3 activation is initiated by signal-dependent phase separation.
• ZDHHC7-mediated palmitoylation and a specific IDR region in NLRP3 are critical for its activation.
• Diverse NLRP3 agonists induce conformational changes leading to phase separation and activation.
• Amphiphilic molecules and chemotherapeutic drugs can directly induce NLRP3 phase separation and activation, independent of ZDHHC7.

Conclusions:

• NLRP3 phase separation is the central mechanism for its activation by diverse stimuli.
• Palmitoylation by ZDHHC7 primes NLRP3 for activation by lowering the phase separation threshold.
• Amphiphilic molecules offer an alternative pathway to directly induce NLRP3 phase separation and activation.