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Molecular and Cellular Biology, February 2003, p. 1428-1440, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1428-1440.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Two Adjacent Trimeric Fas Ligands Are Required for Fas Signaling and Formation of a Death-Inducing Signaling Complex

Nils Holler,1 Aubry Tardivel,1 Magdalena Kovacsovics-Bankowski,1 Sylvie Hertig,1 Olivier Gaide,1 Fabio Martinon,1 Antoine Tinel,1 David Deperthes,1 Silvio Calderara,2 Therese Schulthess,3 Jürgen Engel,3 Pascal Schneider,1* and Jürg Tschopp1

Institute of Biochemistry, BIL Biomedical Research Center, University of Lausanne,1 Apotech Corporation, CH-1066 Epalinges,2 Biozentrum, CH-4000 Basel, Switzerland3

Received 30 August 2002/ Returned for modification 1 October 2002/ Accepted 21 November 2002

The membrane-bound form of Fas ligand (FasL) signals apoptosis in target cells through engagement of the death receptor Fas, whereas the proteolytically processed, soluble form of FasL does not induce cell death. However, soluble FasL can be rendered active upon cross-linking. Since the minimal extent of oligomerization of FasL that exerts cytotoxicity is unknown, we engineered hexameric proteins containing two trimers of FasL within the same molecule. This was achieved by fusing FasL to the Fc portion of immunoglobulin G1 or to the collagen domain of ACRP30/adiponectin. Trimeric FasL and hexameric FasL both bound to Fas, but only the hexameric forms were highly cytotoxic and competent to signal apoptosis via formation of a death-inducing signaling complex. Three sequential early events in Fas-mediated apoptosis could be dissected, namely, receptor binding, receptor activation, and recruitment of intracellular signaling molecules, each of which occurred independently of the subsequent one. These results demonstrate that the limited oligomerization of FasL, and most likely of some other tumor necrosis factor family ligands such as CD40L, is required for triggering of the signaling pathways.

* Corresponding author. Mailing address: Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Phone: 41 21 692 5709. Fax: 41 21 692 5705. E-mail: pascal.schneider{at}ib.unil.ch.

Molecular and Cellular Biology, February 2003, p. 1428-1440, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1428-1440.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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