CELL BIOLOGY AND METABOLISM
Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival*

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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-α, 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-α 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.

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*

This work was supported in part by a grant from Glaxo-Wellcome (to C. P. B.), by National Institutes of Health NIAID Grant AI44264 (to Y. C.), and by National Science Foundation Grant DBI-942013 (to P. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

c

Supported in part by National Institutes of Health MSTP Training Grant 5T32GM07739-17 and the Robert Wood Johnson Jr. Charitable Trust Endowment Fund,

d

The first and second authors contributed equally to this report.

f

Supported by National Institutes of Health Medical Scientist Training Program Training Grant 5T32GM07739-17.

j

Supported in part by National Institutes of Health Medical Scientist Training Program Training Grant 5T32GM07739-17 and the Louis and Rachel Rudin Family Foundation.

k

Supported by Memorial Sloan-Kettering Cancer Center Support Grant NCI-P30-CA-08748.

m

An investigator of the Howard Hughes Medical Institute.