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Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss

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Abstract

Fas-induced apoptosis is initiated through the recruitment of FADD and procaspase 8 to form the death-inducing signaling complex (DISC). In some cells (type I cells) the initiator caspase 8 directly activates effector caspases such as procaspase 3, whereas in others (type II cells) the death signal is amplified through mitochondria. In epithelial cells, Fas-induced hierarchic caspase activation is also linked with DEDD, a member of the DED family that binds to keratin (K) intermediate filaments (IFs). Hepatocytes are type II cells and their IFs are made exclusively of K8/K18. We have shown previously that K8-null mouse hepatocytes, lacking K8/K18 IFs, are more sensitive than their wild-type counterparts to Fas-induced apoptosis. Here, by examining the cell-death kinetics and death-signaling ordering, we found that K8-null hepatocytes exhibited prominent DISC formation, higher procaspase 8 activation and direct procaspase 3 activation as reported for type I cells; however they experienced a reduced Bid cleavage and a stronger procaspase 9 activation. In addition, the K8/K18 loss altered the DEDD ubiquitination status and nuclear/cytoplasmic distribution. Together, the results suggest that the K8/K18 loss induces a switch in Fas-induced death signaling, likely through a DEDD involvement.

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Acknowledgements

We thank H. Baribault for the gift of the K8-null mice, R. Kemler for the TROMA-1 hybridoma, and M. E. Peter for the anti-DEDD polyclonal antibody. We also thank S. Champetier for producing the K8-containing retrovirus and D. Poirier for providing the cyt c immunofluorescence protocol. We are grateful to J. Lavoie and L. Galarneau for helpful discussions and critical reading of the manuscript. This work was supported by a grant from Canadian Institutes of Health Research.

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  1. Département de Médecine, Centre de Recherche en Cancérologie, Université Laval, Quebec City, QC, Canada

    Stéphane Gilbert & Normand Marceau

  2. Centre de Recherche du Centre Hospitalier, Universitaire de Québec (L’Hôtel-Dieu de Québec), 9 rue McMahon, Quebec City, QC, Canada, G1R 2J6

    Stéphane Gilbert, Alexandre Ruel, Anne Loranger & Normand Marceau

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  1. Stéphane Gilbert
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  2. Alexandre Ruel
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Correspondence to Normand Marceau.

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Gilbert, S., Ruel, A., Loranger, A. et al. Switch in Fas-activated death signaling pathway as result of keratin 8/18-intermediate filament loss. Apoptosis 13, 1479–1493 (2008). https://doi.org/10.1007/s10495-008-0274-x

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