Generation of biologically active interleukin-1beta by meprin B.
ABSTRACT Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that is synthesized as an inactive precursor molecule that must be proteolytically processed to generate the biologically active form. Maturation of the precursor is primarily performed by caspase-1, an intracellular cysteine protease; however, processing by other proteases has been described. Meprins are cell surface and secreted metalloproteases expressed by renal and intestinal brush-border membranes, leukocytes, and cancer cells. In this study we show that purified recombinant meprin B can process the interleukin-1beta precursor to a biologically active form. Amino-terminal sequencing and mass spectrometry analysis of the product of digestion by activated meprin B determined that proteolytic cleavage resulted in an additional six amino acids relative to the site utilized by caspase-1. The biological activity of the meprin B-cleaved cytokine was confirmed by measuring the proliferative response of helper T-cells. These results suggest that meprin may play an important role in activation of this proinflammatory cytokine in various pathophysiological conditions.
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- "Meprin A and filamin C were also elevated in patients with incomplete presentations of KD, suggesting that these markers may be used to improve the diagnosis of incomplete presentations of KD. Similarly, meprin A is a protease that regulates a variety of inflammatory cytokines, including biologically active IL-1b, a key pro-inflammatory cytokine (Herzog et al, 2005), polymorphisms of which have been associated with resistance to treatment of KD (Weng et al, 2010). Thus, meprin A may contribute to the initiation, propagation or compensatory "
ABSTRACT: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97-1 and 0.95-1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease.EMBO Molecular Medicine 02/2013; 5(2). DOI:10.1002/emmm.201201494 · 8.25 Impact Factor
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- "The substrates analyzed are those listed in the paper by (Bertenshaw, Turk et al. 2001). Listed below are substrates and inhibitors of meprin subunits (Bertenshaw, Turk et al. 2001; Kruse, Becker et al. 2004; Herzog, Kaushal et al. 2005; Hirano, Ma et al. 2005). "
ABSTRACT: The astacins are a subfamily of the metzincin superfamily of metalloproteinases. The first to be characterized was the crayfish enzyme astacin. To date more than 200 members of this family have been identified in species ranging from bacteria to humans. Astacins are involved in developmental morphogenesis, matrix assembly, tissue differentiation and digestion. Family members include the procollagen C-proteinase (BMP1, bone morphogenetic protein 1), tolloid and mammalian tolloid-like, HMP (Hydra vulgaris metalloproteinase), sea urchin BP10 (blastula protein) and SPAN (Strongylocentrotus purpuratus astacin), the 'hatching' subfamily comprising alveolin, ovastacin, LCE, HCE ('low' and 'high' choriolytic enzymes), nephrosin (from carp head kidney), UVS.2 from frog, and the meprins. In the human and mouse genomes, there are six astacin family genes (two meprins, three BMP1/tolloid-like, one ovastacin), but in Caenorhabditis elegans there are 40. Meprins are the only astacin proteinases that function on the membrane and extracellularly by virtue of the fact that they can be membrane-bound or secreted. They are unique in their domain structure and covalent subunit dimerization, oligomerization propensities, and expression patterns. They are normally highly regulated at the transcriptional and post-translational levels, localize to specific membranes or extracellular spaces, and can hydrolyse biologically active peptides, cytokines, extracellular matrix (ECM) proteins and cell-surface proteins. The in vivo substrates of meprins are unknown, but the abundant expression of these proteinases in the epithelial cells of the intestine, kidney and skin provide clues to their functions.Molecular Aspects of Medicine 09/2008; 29(5):309-28. DOI:10.1016/j.mam.2008.08.002 · 10.30 Impact Factor
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- "However, this does not apply to promeprin b, whose activation site appears to be inaccessible for peptidases larger than trypsin (Becker et al., 2003). There are various in vitro observations of a cleavage of basement membrane proteins (e.g., collagen IV, nidogen-1, and fibronectin), protein kinases, growth factors, cytokines (interleukin-1b), and other bioactive peptides by meprin, but both subunits exhibit markedly different cleavage specificities (Choudry and Kenny, 1991; Kaushal et al., 1994; Chestukhin et al., 1997; Kö hler et al., 2000; Bertenshaw et al., 2001; Kruse et al., 2004; Herzog et al., 2005). Meanwhile, a broader range of sites of meprin expression other than kidney and intestine has been discovered, which varies between species and between developmental stages within a species. "
ABSTRACT: The zinc endopeptidase meprin (EC 220.127.116.11) is expressed in brush border membranes of intestine and kidney tubules, intestinal leukocytes, and certain cancer cells, suggesting a role in epithelial differentiation and cell migration. Here we show by RT-PCR and immunoblotting that meprin is also expressed in human skin. As visualized by immunohistochemistry, the two meprin subunits are localized in separate cell layers of the human epidermis. Meprin alpha is expressed in the stratum basale, whereas meprin beta is found in cells of the stratum granulosum just beneath the stratum corneum. In hyperproliferative epidermis such as in psoriasis vulgaris, meprin alpha showed a marked shift of expression from the basal to the uppermost layers of the epidermis. The expression patterns suggest distinct functions for the two subunits in skin. This assumption is supported by diverse effects of recombinant meprin alpha and beta on human adult low-calcium high-temperature keratinocytes. Here, beta induced a dramatic change in cell morphology and reduced the cell number, indicating a function in terminal differentiation, whereas meprin alpha did not affect cell viability, and may play a role in basal keratinocyte proliferation.Journal of Investigative Dermatology 06/2007; 127(5):1115-25. DOI:10.1038/sj.jid.5700675 · 6.37 Impact Factor