Abstract
Proprotein convertases (PCs) have been proposed to play a role in tumor necrosis factor-alpha converting enzyme (TACE) processing/activation. Using the furin-deficient LoVo cells, as well as the furin-proficient synoviocytes and HT1080 cells expressing the furin inhibitor alpha(1)-PDX, we demonstrate that furin activity alone is not sufficient for effective maturation and activation of the TACE enzyme. Data from in vitro and in vivo cleavage assays indicate that PACE-4, PC5/PC6, PC1 and PC2 can directly cleave the TACE protein and/or peptide. PC inhibition in macrophages reduced the release of soluble TNF-alpha from transmembrane pro-TNF-alpha. We therefore conclude that furin, in addition to other candidate PCs, is involved in TACE maturation and activation.
MeSH terms
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ADAM Proteins
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ADAM17 Protein
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Amino Acid Sequence
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Animals
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Cell Line, Tumor
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Activation / physiology
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Enzyme Precursors / chemistry
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Enzyme Precursors / metabolism*
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Furin / antagonists & inhibitors
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Furin / deficiency
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Furin / genetics
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Furin / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / physiology
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Humans
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Jurkat Cells
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Metalloendopeptidases / chemistry
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Metalloendopeptidases / metabolism*
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Proprotein Convertases / antagonists & inhibitors
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Proprotein Convertases / genetics
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Proprotein Convertases / metabolism*
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Protease Inhibitors / pharmacology
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Rats
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Receptors, Tumor Necrosis Factor / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Synovial Membrane / cytology
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Transfection
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Tumor Necrosis Factor-alpha / metabolism*
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alpha 1-Antitrypsin / genetics
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alpha 1-Antitrypsin / pharmacology
Substances
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Enzyme Precursors
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Protease Inhibitors
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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alpha 1-Antitrypsin
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Proprotein Convertases
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Furin
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ADAM Proteins
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Metalloendopeptidases
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, rat