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Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex.


ABSTRACT: 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.

SUBMITTER: Holler N 

PROVIDER: S-EPMC141146 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex.

Holler Nils N   Tardivel Aubry A   Kovacsovics-Bankowski Magdalena M   Hertig Sylvie S   Gaide Olivier O   Martinon Fabio F   Tinel Antoine A   Deperthes David D   Calderara Silvio S   Schulthess Therese T   Engel Jürgen J   Schneider Pascal P   Tschopp Jürg J  

Molecular and cellular biology 20030201 4


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  ...[more]

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