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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

Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
Nature (Impact Factor: 42.35). 04/1992; 356(6372):768-774. DOI: 10.1038/356768a0

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.

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    • "ASC contains an N-terminal PYD and a C-terminal caspase recruitment domain (CARD) [3]. CASP1 consists of a CARD and catalytic domains (p10 and p20) [4] [5]. Notably, each inflammasome component possesses oligomerization activity. "
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    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 [34]. "
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    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 [27]. Surprisingly, increased expression of CASP1 has been reported to be a frequent event in CP [28]. "
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Kevin Tyler Chapman