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

doi:10.1074/jbc.274.19.13613

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*

From the ^tOaTri-Institutional (Cornell/Rockefeller University/Memorial Sloan-Kettering Cancer Center) M.D./Ph.D. Training Program, New York, New York 10021, the ^tObCellular Biochemistry and Biophysics Program and ⁱMolecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, the ^tOhDepartment of Molecular Biochemistry, Glaxo Wellcome Research and Development Inc., Research Triangle Park, North Carolina 27709, and the ^tOeLaboratory of Immunology, ^tOgLaboratory of Cellular Physiology and Immunology, and ^tOlHoward Hughes Medical Institute, Rockefeller University, New York, New York 10021

Abstract

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.

Footnotes

↵* 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.
↵FNc Supported in part by National Institutes of Health MSTP Training Grant 5T32GM07739-17 and the Robert Wood Johnson Jr. Charitable Trust Endowment Fund,
↵FNd The first and second authors contributed equally to this report.
↵FNf Supported by National Institutes of Health Medical Scientist Training Program Training Grant 5T32GM07739-17.
↵FNj Supported in part by National Institutes of Health Medical Scientist Training Program Training Grant 5T32GM07739-17 and the Louis and Rachel Rudin Family Foundation.
↵FNk Supported by Memorial Sloan-Kettering Cancer Center Support Grant NCI-P30-CA-08748.
↵m An investigator of the Howard Hughes Medical Institute.
↵FNn To whom correspondence should be addressed: Cellular Biochemistry and Biophysics Program, Sloan-Kettering Inst., Memorial Sloan-Kettering Cancer Center, Box 368, 1275 York Ave., New York, NY 10021. Tel.: 212-639-2915; Fax: 212-717-3047; E-mail:c-blobel{at}ski.mskcc.org.
Abbreviations:

TNF

tumor necrosis factor

TRANCE

TNF-related activation-induced cytokine

TRANCE-R

TRANCE receptor

TACE

TNF-α convertase

OPG/OCIF

osteoprotegerin/osteoclast inhibitory factor

βAPP

β-amyloid precursor protein

PBS

phosphate-buffered saline

GST

glutathioneS-transferase

mAb

monoclonal antibody

DC

dendritic cell

PAGE

polyacrylamide gel electrophoresis

STI

soybean trypsin inhibitor

TPCK

N-tosyl-l-phenylalanine chloromethyl ketone

TPA

12-O-tetradecanoylphorbol-13-acetate
- Received February 2, 1999.
The American Society for Biochemistry and Molecular Biology, Inc.