TACE/ADAM-17 maturation and activation of sheddase activity require proprotein convertase activity.
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.
Srour
Nadim
N
Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
Lebel
Annie
A
McMahon
Stephanie
S
Fournier
Isabelle
I
Fugère
Martin
M
Day
Robert
R
Dubois
Claire M
CM
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004792:Enzyme Precursors / Q000737:chemistry / Q000378:metabolism*; D045683:Furin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000494:pharmacology
D004792:Enzyme Precursors; D011480:Protease Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000515:alpha 1-Antitrypsin; D043484:Proprotein Convertases; D045683:Furin; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat