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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/NLRP1_HUMAN NLRP1_HUMAN] As the sensor component of the NLRP1 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762).[UniProtKB:A1Z198]<ref>PMID:11113115</ref> <ref>PMID:15212762</ref> <ref>PMID:17349957</ref> <ref>PMID:17418785</ref> <ref>PMID:18511561</ref> <ref>PMID:19651869</ref> <ref>PMID:22665479</ref> <ref>PMID:27662089</ref> | [https://www.uniprot.org/uniprot/NLRP1_HUMAN NLRP1_HUMAN] As the sensor component of the NLRP1 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762).[UniProtKB:A1Z198]<ref>PMID:11113115</ref> <ref>PMID:15212762</ref> <ref>PMID:17349957</ref> <ref>PMID:17418785</ref> <ref>PMID:18511561</ref> <ref>PMID:19651869</ref> <ref>PMID:22665479</ref> <ref>PMID:27662089</ref> | ||
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== Publication Abstract from PubMed == | |||
Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis(1). NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer(2-6). However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated(4,7,8). 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 basis for thioredoxin-mediated suppression of NLRP1 inflammasome.,Zhang Z, Shibata T, Fujimura A, Kitaura J, Miyake K, Ohto U, Shimizu T Nature. 2023 Oct;622(7981):188-194. doi: 10.1038/s41586-023-06532-4. Epub 2023 , Sep 13. PMID:37704723<ref>PMID:37704723</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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==See Also== | |||
*[[Thioredoxin 3D structures|Thioredoxin 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||