Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes |
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Authors: | Karine Sá Ferreira Clemens Kreutz Sabine MacNelly Karin Neubert Angelika Haber Matthew Bogyo " target="_blank">Jens Timmer " target="_blank">Christoph Borner |
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Institution: | 1.Institute of Molecular Medicine and Cell Research,University of Freiburg,Freiburg,Germany;2.GRK 1104, From Cells to Organs: Molecular Mechanisms of Organogenesis, Faculty of Biology,University of Freiburg,Freiburg,Germany;3.Institute for Physics,University of Freiburg,Freiburg,Germany;4.Freiburg Center for Systems Biology (ZBSA),University of Freiburg,Freiburg,Germany;5.Internal Medicine,University Hospital of Freiburg,Freiburg,Germany;6.Department of Pathology, School of Medicine,Stanford University,Stanford,USA;7.Freiburg Institute for Advanced Studies (FRIAS),University of Freiburg,Freiburg,Germany;8.BIOSS Centre for Biological Signalling Studies,University of Freiburg,Freiburg,Germany;9.Department of Clinical and Experimental Medicine,Link?ping University,Link?ping,Sweden;10.Spemann Graduate School of Biology and Medicine (SGBM),University of Freiburg,Freiburg,Germany |
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Abstract: | The TNF-R1 like receptor Fas is highly expressed on the plasma membrane of hepatocytes and plays an essential role in liver
homeostasis. We recently showed that in collagen-cultured primary mouse hepatocytes, Fas stimulation triggers apoptosis via
the so-called type I extrinsic signaling pathway. Central to this pathway is the direct caspase-8-mediated cleavage and activation
of caspase-3 as compared to the type II pathway which first requires caspase-8-mediated Bid cleavage to trigger mitochondrial
cytochrome c release for caspase-3 activation. Mathematical modeling can be used to understand complex signaling systems such as crosstalks
and feedback or feedforward loops. A previously published model predicted a positive feedback loop between active caspases-3
and -8 in both type I and type II FasL signaling in lymphocytes and Hela cells, respectively. Here we experimentally tested
this hypothesis in our hepatocytic type I Fas signaling pathway by using wild-type and XIAP-deficient primary hepatocytes
and two recently characterized, selective caspase-3/-7 inhibitors (AB06 and AB13). Caspase-3/-7 activity assays and quantitative
western blotting confirmed that fully processed, active p17 caspase-3 feeds back on caspase-8 by cleaving its partially processed
p43 form into the fully processed p18 species. Our data do not discriminate if p18 positively or negatively influences FasL-induced
apoptosis or is responsible for non-apoptotic aspects of FasL signaling. However, we found that caspase-3 also feeds back
on Bid and degrades its own inhibitor XIAP, both events that may enhance caspase-3 activity and apoptosis. Thus, potent, selective
caspase-3 inhibitors are useful tools to understand complex signaling circuitries in apoptosis. |
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