A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes

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.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging- or tau-mediated memory deficits via IL-1β upregulation in mice. Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1β proximal promoter. In humans, hypomethylation of IL-1β is strongly associated with chronological age and with elevated IL-1β transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases. Copyright © 2015 the authors 0270-6474/15/350807-12$15.00/0.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clan CD forms a structural group of cysteine peptidases, containing seven individual families and two subfamilies of structurally related enzymes. Historically, it is most notable for containing the mammalian caspases, on which the structures of the clan were founded. Interestingly, the caspase family is split into two subfamilies: the caspases, and a second subfamily containing both the paracaspases and the metacaspases. Structural data are now available for both the paracaspases and the metacaspases, allowing a comprehensive structural analysis of the entire caspase family. In addition, a relative plethora of structural data has recently become available for many of the other families in the clan, allowing both the structures and the structure-function relationships of clan CD to be fully explored. The present review compares the enzymes in the caspase subfamilies with each other, together with a comprehensive comparison of all the structural families in clan CD. This reveals a diverse group of structures with highly conserved structural elements that provide the peptidases with a variety of substrate specificities and activation mechanisms. It also reveals conserved structural elements involved in substrate binding, and potential autoinhibitory functions, throughout the clan, and confirms that the metacaspases are structurally diverse from the caspases (and paracaspases), suggesting that they should form a distinct family of clan CD peptidases.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.Cell Death and Differentiation advance online publication, 19 December 2014; doi:10.1038/cdd.2014.216.
    Cell Death and Differentiation 12/2014; 22(4). DOI:10.1038/cdd.2014.216 · 8.39 Impact Factor

Kevin Tyler Chapman