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-Mediated Lysosomal Permeabilization Is FAN and Caspase 8/Bid-Dependent
1 Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
2 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: gores.gregory{at}mayo.edu.
TNF
cytotoxic signaling involves lysosomal permeabilization with release of the
lysosomal protease cathepsin B (ctsb) into the cytosol. However, the mechanisms mediating
lysosomal breakdown remain unclear. As caspase-8 and factor associated with neutral
sphingomyelinase activation (FAN) have been implicated as proximal mediators of TNF-
associated apoptosis, their role in lysosomal permeabilization was examined. The cellular
distribution of cathepsin B-green fluorescent protein (ctsb-GFP) in a rat hepatoma cell line was
imaged by confocal microscopy. Ctsb-GFP fluorescence was punctate under basal conditions
but became diffuse following treatment with TNF/actinomycin D. This cellular redistribution
of ctsb-GFP was blocked by transfection with a vector expressing a dominant negative Fas-associated
protein with death domain (
FADD), CrmA or a pharmacologic caspase-8 inhibitor,
IETD-fmk. Consistent with the concept that caspase 8-mediated apoptosis is also Bid-dependent
in hepatocytes, ctsb-GFP release from lysosomes was reduced in hepatocytes from Bid -/- mice.
Interestingly, transfection with a vector expressing a dominant negative FAN (FAN) also
blocked ctsb-GFP release and caspase-8 activation. Paradigms that inhibited ctsb-GFP release
from lysosomes also reduced apoptosis as assessed by morphology and biochemical criteria. In
conclusion, these studies suggest FAN is upstream of caspase-8/Bid in a signaling cascade
culminating in lysosomal permeabilization.
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