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Biologically Active Fas Antigen and Its Cognate Ligand Are
Expressed on Plasma Membrane-Derived Extracellular Vesicles
Joseph Albanese,
Sarkis Meterissian,
Maria Kontogiannea,
Catherine Dubreuil,
Arthur Hand,
Sandra Sorba, and
Nicholas Dainiak
From the Departments of Medicine and Surgery, Royal Victoria
Hospital, McGill University, Montreal, Quebec, Canada; the Department
of Pediatric Dentistry, University of Connecticut Health Center,
Farmington, CT; and the Department of Medicine, Bridgeport Hospital,
Yale University School of Medicine, Bridgeport, CT.
Exfoliation of plasma membrane components is a directed process that
consumes energy and requires active cell metabolism. Proteins involved
in regulating the survival and proliferation of eukaryotic cells are
released on exfoliated vesicles. We examine here whether the Fas
receptor and its cognate ligand (FasL) are present on vesicles shed
from high metastatic potential CX-1 cells and low metastatic potential
MIP-101 cells and from HuT 78 cells, respectively. Rates of exfoliation
at 2 hours and cumulative levels of extracellular vesicles in
serum-free medium conditioned by CX-1 cells are increased by 1.8-fold
and 1.6-fold, respectively, relative to that in medium conditioned by
MIP-101 cells. Although vesicles shed from both cancer cell lines
contain Fas antigen, the amount of Fas per vesicle and the percentage
of vesicles containing Fas are increased for vesicles isolated from
MIP-101 cells, relative to those from CX-1 cells, as determined by
immunogold particle labeling and electron microscopy and by
immunofluorescence microscopy and flow cytometry. Results of metabolic
labeling with 35S-methionine indicate that Fas biosynthesis
is reduced by up to 3.3-fold for CX-1 cells, relative to that of
MIP-101 cells, consistent with the finding of decreased Fas on vesicles
shed from the plasma membrane of CX-1 cells. Although mRNA for soluble
Fas receptor is detectable in both cell lines, depletion of shed
vesicles from serum-free medium by ultracentrifugation removes all
detectable biological activity. FasL is detected on vesicles exfoliated
from HuT 78 cells by immunoelectron microscopy and Western blot
analysis. FasL-bearing vesicles induce apoptosis of Fas-expressing
cancer cells at the same level as observed by treatment with monoclonal anti-Fas antibody. Furthermore, Fas-bearing extracellular vesicles from
MIP-101 but not from CX-1 cells protect the CX-1 cell line from
FasL-induced and anti-Fas-mediated apoptosis, indicating that Fas
present on shed vesicles is biologically active. We conclude that the
Fas antigen and its cognate ligand are exfoliated from the cell surface
in a bioactive configuration. Exfoliation may provide a mechanism for
long-range signal-directed apoptosis while maintaining Fas/FasL on a
membrane surface.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3862-3874
© 1998 by The American Society of Hematology.
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