AMBRA1 allosterically activates NLRP3 by releasing its autoinhibition.

AMBRA1 allosterically activates NLRP3 by destabilizing its autoinhibited conformation, promoting transition to an active state in inflammatory responses.

• Why it matters: Understanding how NLRP3 is released from its autorepressed state is crucial for developing therapies for inflammatory diseases linked to NLRP3 dysfunction.
• What they did: The study used biochemical and cellular approaches to show that AMBRA1 binds NLRP3 via its β-propeller domain, destabilizes its closed conformation, and enhances ATP binding, thereby activating NLRP3.
• The result: AMBRA1 deficiency impairs NLRP3 activation and reduces inflammation in mouse models, while nanobodies blocking their interaction inhibit NLRP3 activation, highlighting therapeutic potential.