FasR stimulation by Fas ligand leads to rapid formation of FasR microaggregates, 
which become signaling protein oligomerization transduction structures (SPOTS), 
through interactions with actin and ezrin, a structural step that triggers 
death-inducing signaling complex formation, in association with procaspase-8 
activation. In some cells, designated as type I, caspase 8 directly activates 
effector caspases, whereas in others, known as type II, the caspase-mediated 
death signaling is amplified through mitochondria. Keratins are the intermediate 
filament (IF) proteins of epithelial cells, expressed as pairs in a 
lineage/differentiation manner. Hepatocyte IFs are made solely of keratins 8/18 
(K8/K18), the hallmark of all simple epithelia. We have shown recently that in 
comparison to type II wild-type (WT) mouse hepatocytes, the absence of K8/K18 
IFs in K8-null hepatocytes leads to more efficient FasR-mediated apoptosis, in 
link with a type II/type I-like switch in FasR-death signaling. Here, we 
demonstrate that the apoptotic process occurring in type I-like K8-null 
hepatocytes is associated with accelerated SPOTS elaboration at surface 
membrane, along with manifestation of FasR cap formation and internalization. In 
addition, the lipid raft organization is altered in K8-null hepatocytes. While 
lipid raft inhibition impairs SPOTS formation in both WT and K8-null 
hepatocytes, the absence of K8/K18 IFs in the latter sensitizes SPOTS to actin 
de-polymerization, and perturbs ezrin compartmentalization. Overall, the results 
indicate that the K8/K18 IF loss in hepatocytes alters the initial FasR 
activation steps through perturbation of ezrin/actin interplay and lipid raft 
organization, which leads to a type II/type I switch in FasR-death signaling.