A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells

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Abstract
Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins1. Modification of the cell surface in this way can alter the cell's responsiveness to its environment2 and release potent soluble regulatory factors3. The release of soluble tumour-necrosis factor-α (TNF-α) from its membrane-bound precursor4,5 is one of the most intensively studied shedding events because this inflammatory cytokine is so physiologically important6,7. The inhibition of TNF-α release (and many other shedding phenomena) by hydroxamic acid-based inhibitors indicates that one or more metalloproteinases is involved3,8,9. We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-α. Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-α production. This enzyme (called the TNF-α-converting enzyme, or TACE) is a new member of the family of mammalian adama-lysins (or ADAMs)10, for which no physiological catalytic function has previously been identified. Our results should facilitate the development of therapeutically useful inhibitors of TNF-α release, and they indicate that an important function of adamalysins may be to shed cell-surface proteins.
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