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

Apoptosis. 2008 Dec;13(12):1479-93. doi: 10.1007/s10495-008-0274-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / metabolism
  • Apoptosis / physiology*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Caspases / metabolism
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Enzyme Activation
  • Hepatocytes / cytology
  • Hepatocytes / physiology
  • Intermediate Filaments / metabolism*
  • Keratin-18 / genetics
  • Keratin-18 / metabolism*
  • Keratin-8 / genetics
  • Keratin-8 / metabolism*
  • Mice
  • Mice, Knockout
  • Signal Transduction / physiology*
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • Antibodies
  • BH3 Interacting Domain Death Agonist Protein
  • Death Domain Receptor Signaling Adaptor Proteins
  • Dedd protein, mouse
  • Keratin-18
  • Keratin-8
  • fas Receptor
  • Cytochromes c
  • Caspases