Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ et al.. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356: 768-774
ABSTRACT Interleukin-1β (IL-1β)-converting enzyme cleaves the
IL-1β precursor to mature IL-1β, an important mediator of
inflammation. The identification of the enzyme as a unique cysteine
protease and the design of potent peptide aldehyde inhibitors are
described. Purification and cloning of the complementary DNA indicates
that IL-lβ-converting enzyme is composed of two nonidentical
subunits that are derived from a single proenzyme, possibly by
autoproteolysis. Selective inhibition of the enzyme in human blood
monocytes blocks production of mature IL-1β, indicating that it is
a potential therapeutic target.
- SourceAvailable from: Motoi Kobayashi
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- "ASC contains an N-terminal PYD and a C-terminal caspase recruitment domain (CARD) . CASP1 consists of a CARD and catalytic domains (p10 and p20)  . Notably, each inflammasome component possesses oligomerization activity. "
ABSTRACT: Increasing evidence indicates that caspase recruitment domain (CARD)-mediated caspase-1 (CASP1) assembly is an essential process for its activation and subsequent interleukin (IL)-1β release, leading to the initiation of inflammation. Both CARD16 and CARD17 were previously reported as inhibitory homologs of CASP1; however, their molecular function remains unclear. Here, we identified that oligomerization activity allows CARD16 to function as a CASP1 activator. We investigated the molecular characteristics of CARD16 and CARD17 in transiently transfected HeLa cells. Although both CARD16 and CARD17 interacted with CASP1CARD, only CARD16 formed a homo-oligomer. Oligomerized CARD16 formed a filament-like structure with CASP1CARD and a speck with apoptosis-associated speck-like protein containing a CARD. A filament-like structure formed by CARD16 promoted CASP1 filament assembly and IL-1β release. In contrast, CARD17 did not form a homo-oligomer or filaments and inhibited CASP1-dependent IL-1β release. Mutated CARD16D27G, mimicking the CARD17 amino acid sequence, formed a homo-oligomer but failed to form a filament-like structure. Consequently, CARD16D27G weakly promoted CASP1 filament assembly and subsequent IL-1β release. These results suggest that oligomerized CARD16 promotes CARD-mediated molecular assembly and CASP1 activation.FEBS Open Bio 04/2015; 5. DOI:10.1016/j.fob.2015.04.011 · 1.52 Impact Factor
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- "As a common substrate of various inflammasomes, pro-caspase-1 is converted to its active form, caspase-1 (consisting of p20 and p10 heterotetramers). Caspase-1 cleaves intracellular pro-IL-1β to yield the mature, active IL-1β (p17), which is secreted into the extracellular space . "
ABSTRACT: Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid [siRNA]) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-chalenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.PLoS ONE 09/2014; 9(9):e107639. DOI:10.1371/journal.pone.0107639 · 3.23 Impact Factor
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- "CHSY1 was one of the significant genes in cluster D and was enriched and regulated by miR-124a. Researchers in a previous study demonstrated that CHSY1 regulated its downstream target CASP1 (caspase 1, also known as interleukin 1β–converting enzyme), which could cleave interleukin 1β precursors into mature cytokines and contribute to inflammation . Surprisingly, increased expression of CASP1 has been reported to be a frequent event in CP . "
ABSTRACT: Background Diagnosis at an early stage of chronic pancreatitis (CP) is challenging. It has been reported that microRNAs (miRNAs) are increasingly found and applied as targets for the diagnosis and treatment of various cancers. However, to the best of our knowledge, few published papers have described the role of miRNAs in the diagnosis of CP. Method We downloaded gene expression profile data from the Gene Expression Omnibus and identified differentially expressed genes (DEGs) between CP and normal samples of Harlan mice and Jackson Laboratory mice. Common DEGs were filtered out, and the semantic similarities of gene classes were calculated using the GOSemSim software package. The gene class with the highest functional consistency was selected, and then the Lists2Networks web-based system was used to analyse regulatory relationships between miRNAs and gene classes. The functional enrichment of the gene classes was assessed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway annotation terms. Results A total of 405 common upregulated DEGs and 7 common downregulated DEGs were extracted from the two kinds of mice. Gene cluster D was selected from the common upregulated DEGs because it had the highest semantic similarity. miRNA 124a (miR-124a) was found to have a significant regulatory relationship with cluster D, and DEGs such as CHSY1 and ABCC4 were found to be regulated by miR-124a. The GO term of response to DNA damage stimulus and the pathway of Escherichia coli infection were significantly enriched in cluster D. Conclusion DNA damage and E. coli infection might play important roles in CP pathogenesis. In addition, miR-124a might be a potential target for the diagnosis and treatment of CP.European journal of medical research 05/2014; 19(1):31. DOI:10.1186/2047-783X-19-31 · 1.50 Impact Factor
Kevin Tyler Chapman