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Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome

Author

Listed:
  • 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
    Juntendo University Graduate School of Medicine)

  • Kensuke Miyake

    (The University of Tokyo)

  • Umeharu Ohto

    (The University of Tokyo)

  • Toshiyuki Shimizu

    (The University of Tokyo)

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.

Suggested Citation

  • Zhikuan Zhang & Takuma Shibata & Akiko Fujimura & Jiro Kitaura & Kensuke Miyake & Umeharu Ohto & Toshiyuki Shimizu, 2023. "Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome," Nature, Nature, vol. 622(7981), pages 188-194, October.
    • Handle: RePEc:nat:nature:v:622:y:2023:i:7981:d:10.1038_s41586-023-06532-4
    DOI: 10.1038/s41586-023-06532-4
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    Cited by:

    1. Yulin Zhang & Kaiyan Xi & Zhipeng Fu & Yuying Zhang & Bo Cheng & Fan Feng & Yuanmin Dong & Zezheng Fang & Yi Zhang & Jianyu Shen & Mingrui Wang & Xu Han & Huimin Geng & Lei Sun & Xingang Li & Chen Che, 2024. "Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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