Involvement of FAN in TNF-induced apoptosis

B Ségui

O Cuvillier

S Adam-Klages

V Garcia

R Salvayre+2 authors

^{Institut National de la Santé et de la Recherche Médicale (INSERM) U466, Centre Hospitalier Universitaire Rangueil, Toulouse, France}^{Institut für Immunologie, Christian-Albrechts Universität, Kiel, Germany}^{INSERM U28, CHU Purpan, Toulouse, France}^{Institut für Medizinische Mikrobiologie und Hygiene, Cologne, Germany}

Address correspondence to: Thierry Levade, INSERM U466, CHU Rangueil, 1 Ave Poulhès, 31403 Toulouse, France. Phone: 33-561-32-20-60; Fax: 33-561-32-20-84; E-mail: rf.mresni.lieugnar@edavel.

Received 2000 Oct 6; Accepted 2001 May 21.

Abstract

TNF-α is a pleiotropic cytokine activating several signaling pathways initiated at distinct intracellular domains of the TNF receptors. Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated. The roles of this region and of the associated adapter protein FAN (factor associated with neutral SMase activation) in the cytotoxic response to TNF have been investigated. We have now shown that stable expression in human fibroblasts of a dominant negative form of FAN abrogates TNF-induced ceramide generation from sphingomyelin hydrolysis and reduces caspase processing, thus markedly inhibiting TNF-triggered apoptosis. However, the cytotoxic responses to daunorubicin and exogenous ceramide remain unaltered, as do the TNF-induced p42/p44 MAPK activation and CD54 expression. Fibroblasts from FAN-knockout mice also proved to be resistant to TNF toxicity. These findings highlight the previously unrecognized role of the adapter protein FAN in signaling cell death induction by TNF.

Abstract

Acknowledgments

We thank N. Andrieu-Abadie for discussion, and D. Nicholson, P. Krammer, G. Cohen, X. Wang, F. Tercé, and D. Perry for providing reagents. The technical assistance of S. Carpentier and M.A. Berges is gratefully acknowledged. This work was supported by grants from INSERM, Université P. Sabatier, VML and ARC. B. Ségui and O. Cuvillier are recipients of MESR and FRM, respectively.

Acknowledgments

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