Self-association of the Death Domains of the p55 Tumor Necrosis Factor (TNF) Receptor and Fas/APO1 Prompts Signaling for TNF and Fas/APO1 Effects

doi:10.1074/jbc.270.1.387

Self-association of the Death Domains of the p55 Tumor Necrosis Factor (TNF) Receptor and Fas/APO1 Prompts Signaling for TNF and Fas/APO1 Effects (*)

From the Department of Membrane Research and Biophysics, The Weizmann Institute of Science, Rehovot 76100, Israel and
Denis Diderot University, INSERM Unit 248, 75010 Paris, France

^¶ To whom correspondence should be addressed. Tel: 972-8-343941. Fax: 972-8-343165.

Abstract

Signaling by the p55 tumor necrosis factor (TNF) receptor and by the structurally related receptor Fas/APO1 is initiated by receptor clustering. Data presented here and in other recent studies (Wallach, D., Boldin, M., Varfolomeev, E. E., Bigda, Y., Camonis, H. J. and Mett, I.(1994) Cytokine 6, 556; Song, H. Y., Dunbar, J. D., and Bonner, D. B.(1994) J. Biol. Chem. 269, 22492-22495) indicate that part of that region within the intracellular domains of the two receptors that is involved in signaling for cell death, as well as for some other effects (the “death domain”, specifically self-associates. We demonstrate also the expected functional consequence of this association; a mere increase in p55 TNF receptor expression, or the expression just of its intracellular domain, is shown to trigger signaling for cytotoxicity as well as for interleukin 8 gene induction, while expression of the intracellular domain of Fas/APO1 potentiates the cytotoxicity of co-expressed p55 TNF receptor. These findings indicate that the p55 TNF and Fas/APO1 receptors play active roles in their own clustering and suggest the existence of cellular mechanisms that restrict the self-association of these receptors, thus preventing constitutive signaling.

Footnotes

↵^§ Equivalent contributions were made by these two authors.
↵* This work was supported in part by grants from Inter-Lab Ltd. (Ness-Ziona, Israel), from Ares Trading S.A. (Switzerland), and from the Israeli Ministry of Arts and Sciences. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

TNF

tumor necrosis factor

AD

activation domain

DBD

DNA binding domain

GST

glutathione S-transferase

IC

intracellular domain

IL-8

interleukin 8

MBP

maltose-binding protein

p55-IC

intracellular domain of the p55-R

p55-R

p55 tumor necrosis factor receptor

ELISA

enzyme-linked immunosorbent assay.
↵² J. Naismith and S. Sprang, personal communication.
- Received October 4, 1994.
- Revision received November 4, 1994.