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Published 28 March 2005. doi:10.1083/jcb.200501048
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 7, 1087-1098
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Article

The extracellular domains of FasL and Fas are sufficient for the formation of supramolecular FasL-Fas clusters of high stability



Frank Henkler1, Eva Behrle2, Kevin M. Dennehy3, Andreas Wicovsky1, Nathalie Peters2, Clemens Warnke1, Klaus Pfizenmaier2, and Harald Wajant1

1 Department of Molecular Internal Medicine, Medical Polyclinic, University of Wuerzburg, 97070 Wuerzburg, Germany
2 Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany
3 Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Wuerzburg, Germany

Correspondence to Harald Wajant: harald.wajant{at}mail.uni-wuerzburg.de

Using fluorescent variants of Fas and FasL, we show that membrane FasL and Fas form supramolecular clusters that are of flexible shape, but nevertheless stable and persistent. Membrane FasL-induced Fas clusters were formed in caspase-8– or FADD-deficient cells or when a cytoplasmic deletion mutant of Fas was used suggesting that cluster formation is independent of the assembly of the cytoplasmic Fas signaling complex and downstream activated signaling pathways. In contrast, cross-linked soluble FasL failed to aggregate the cytoplasmic deletion mutant of Fas, but still induced aggregation of signaling competent full-length Fas. Moreover, membrane FasL-induced Fas cluster formation occurred in the presence of the lipid raft destabilizing component methyl-ß-cyclodextrin, whereas Fas aggregation by soluble FasL was blocked. Together, these data suggest that the extracellular domains of Fas and FasL alone are sufficient to drive membrane FasL-induced formation of supramolecular Fas–FasL complexes, whereas soluble FasL-induced Fas aggregation is dependent on lipid rafts and mechanisms associated with the intracellular domain of Fas.

Abbreviations used in this paper: ßMCD, methyl-ß-cyclodextrin; DISC, death-inducing signaling complex; FADD, Fas-associated death domain; FLIP, fluorescence loss in photobleaching; IAP, inhibitor of apoptosis; ROI, region of interest; SPOTS, signaling protein oligomeric transduction structures.


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