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J. Biol. Chem., Vol. 278, Issue 35, 32801-32809, August 29, 2003
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Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-
-converting Enzyme
IMPLICATIONS FOR CD40 SIGNALING*
||
From the
CNRS UMR 5540, IFR 66, Université
Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France and the
¶Department of Genetics, Osaka University Medical
School, Osaka 565-0871, Japan
The soluble form of CD40 (sCD40), which co-exists with the
membrane-anchored form (mCD40), is a natural antagonist of mCD40/CD154
interaction. However, the mechanism leading to the production of sCD40 has
never been investigated. Here, we show that the engagement of mCD40 on the
surface of B lymphocytes by anti-CD40 antibody led to enhanced sCD40 release
associated with decreased amounts of mCD40. This sCD40 production was not
affected by vesicular traffic inhibitors but was completely blocked by a
broad-spectrum synthetic metalloproteinase (MP) inhibitor (GM6001) or a
membrane-anchored MP-specific inhibitor (dec-RVKR-cmk). Recombinant MP
disintegrin tumor necrosis factor-
converting enzyme (TACE) cleaved the
purified CD40 ectodomain/Fc chimeric protein in vitro, giving rise to
an sCD40 form similar to that shed from B cell cultures. Moreover, spontaneous
production of sCD40 by mCD40-transfected human embryonic kidney cells
(constitutively expressing TACE) was enhanced by the overexpression of TACE
and abrogated by co-transfection with a dominant-negative TACE mutant. These
results provide strong evidence that sCD40 production is an active process
regulated by the engagement of mCD40 and its proteolytic cleavage by TACE or a
related MP disintegrin. Given the antagonistic activity of sCD40 on the
CD40/CD154 interaction, this shedding mechanism might represent an important
negative feedback control of CD40 functions.
Received for publication, September 30, 2002 , and in revised form, June 3, 2003.
* This work was supported in part by grants from the Ligue Nationale contre le Cancer (comité de la Gironde) and the Etablissement Français des Greffes. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Supported by a grant from the Fondation pour la Recherche Médicale
and the Ligue Nationale contre le Cancer.
|| To whom correspondence should be addressed. Tel.: 33-5-57-57-14-71; Fax: 33-5-57-57-14-72; E-mail: julie.dechanet{at}umr5540.u-bordeaux2.fr.
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