Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival.
Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family, is a dendritic cell survival factor and is essential for osteoclastogenesis and osteoclast activation. In this report we demonstrate (i) that TRANCE, like TNF-alpha, is made as a membrane-anchored precursor, which is released from the plasma membrane by a metalloprotease; (ii) that soluble TRANCE has potent dendritic cell survival and osteoclastogenic activity; (iii) that the metalloprotease-disintegrin TNF-alpha convertase (TACE) can cleave immunoprecipitated TRANCE in vitro in a fashion that mimics the cleavage observed in tissue culture cells; and (iv) that in vitro cleavage of a TRANCE ectodomain/CD8 fusion protein and of a peptide corresponding to the TRANCE cleavage site by TACE occurs at the same site that is used when TRANCE is shed from cells into the supernatant. We propose that the TRANCE ectodomain is released from cells by TACE or a related metalloprotease-disintegrin, and that this release is an important component of the function of TRANCE in bone and immune homeostasis.
Lum
L
L
Tri-Institutional (Cornell/Rockefeller University/Memorial Sloan-Kettering Cancer Center), Training Program, New York, New York 10021, USA.
Wong
B R
BR
Josien
R
R
Becherer
J D
JD
Erdjument-Bromage
H
H
Schlöndorff
J
J
Tempst
P
P
Choi
Y
Y
Blobel
C P
CP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology*; D006801:Humans; D006868:Hydrolysis; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human