Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome

Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis1. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer2-6. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated4,7,8. Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system. Structural and mutational studies and cellular assays show that the inflammasome sensor NLRP1 forms a complex with thioredoxin, which acts as a negative regulator of inflammasome activity.

Automated summary

This study identifies thioredoxin (TRX) as a binder of the inflammasome sensor NLRP1 and a suppressor of NLRP1 inflammasome activity. The oxidized form of TRX binds to the nucleotide-binding domain subdomain of NLRP1, highlighting the essential role of redox-active cysteines of TRX in NLRP1 binding. The findings suggest that the TRX system acts as an intrinsic checkpoint for innate immunity and provides potential targets for future therapeutic intervention in NLRP1 inflammasome activation.