Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

DOI Web Site 1 Citations
  • Daniel P. Ball
    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Lydia P. Tsamouri
    Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Alvin E. Wang
    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Hsin-Che Huang
    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Charles D. Warren
    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Qinghui Wang
    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Isabelle H. Edmondson
    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Andrew R. Griswold
    Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Sahana D. Rao
    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Darren C. Johnson
    Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Daniel A. Bachovchin
    Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Description

<jats:p>The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.</jats:p>

Journal

  • Science Immunology

    Science Immunology 7 (77), eabm7200-, 2022-11-25

    American Association for the Advancement of Science (AAAS)

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