Cutting edge: A dominant negative form of TNF-alpha converting enzyme inhibits ProTNF and TNFRII secretion

TNF-alpha converting enzyme (TACE) is the protease responsible for processi ng proTNF from the 26-kDa membrane-anchored precursor to the secreted 17-kD a TNF-alpha. We show here that a deletion mutant of TACE (dTACE), lacking t he pro and catalytic domains of the protease, acts as a dominant negative f or proTNF processing in transfected HEK293 cells. We used the same system t o test the effect of dTACE on TNFRII processing. Overexpression of dTACE wi th TNFRII resulted in >80% inhibition of TNFRII shedding, Although signific ant inhibition of TNF-alpha and TNFRII shedding was achieved with dTACE, we could not detect a cell surface accumulation of the noncleaved substrates above that observed in the absence of dTACE. Our results suggest that TNFRI I is a substrate for TACE, and that dTACE is capable of interfering,vith th e function of endogenous TACE, either by binding and sequestering TACE subs trates via the disintegrin domain, transmembrane domain, or cytoplasmic tai l, or by some other mechanism that has yet to be determined.