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Structure paper

TitleStructural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.
Journal, issue, pagesNature, Vol. 622, Issue 7981, Page 188-194, Year 2023
Publish dateSep 13, 2023
AuthorsZhikuan Zhang / Takuma Shibata / Akiko Fujimura / Jiro Kitaura / Kensuke Miyake / Umeharu Ohto / Toshiyuki Shimizu /
PubMed AbstractInflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its ...Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis. NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer. However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated. 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.
External linksNature / PubMed:37704723
MethodsEM (single particle)
Resolution3.4 - 3.43 Å
Structure data

32484

7wge

EMDB-32484, PDB-7wge:
Human NLRP1 complexed with thioredoxin
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-35591: Human NLRP1 complexed with thioredoxin (focused map)
Method: EM (single particle) / Resolution: 3.43 Å

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • spodoptera frugiperda (fall armyworm)
KeywordsIMMUNE SYSTEM / NLRP1 / inflammasome / thioredoxin

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