Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome

Zhikuan Zhang, Takuma Shibata, Akiko Fujimura, Jiro Kitaura, Kensuke Miyake, Umeharu Ohto () and Toshiyuki Shimizu ()
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Zhikuan Zhang: The University of Tokyo
Takuma Shibata: The University of Tokyo
Akiko Fujimura: The University of Tokyo
Jiro Kitaura: Juntendo University Graduate School of Medicine
Kensuke Miyake: The University of Tokyo
Umeharu Ohto: The University of Tokyo
Toshiyuki Shimizu: The University of Tokyo

Nature, 2023, vol. 622, issue 7981, 188-194

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06532-4

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