TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity

AbstractProprotein convertases (PCs) have been proposed to play a role in tumor necrosis factor-α 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 α1-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-α from transmembrane pro-TNF-α. We therefore conclude that furin, in addition to other candidate PCs, is involved in TACE maturation and activation