title: Cytoskeleton keratin regulation of FasR signaling through modulation of actin/ezrin interplay at lipid rafts in hepatocytes.
abstract: 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.
authors.affiliation: Centre de Recherche en Cancérologie de l'Université Laval, and Centre de Recherche du Centre Hospitalier de Québec (CRCHUQ)/HDQ, 9 rue McMahon, Quebec, G1R 2J6, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gilbert
authors.forename: Anne
authors.initials: A
authors.lastname: Loranger
authors.forename: Josée N
authors.initials: JN
authors.lastname: Lavoie
authors.forename: Normand
authors.initials: N
authors.lastname: Marceau
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004058:Diffusion; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007382:Intermediate Filaments / Q000378:metabolism*; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000172:deficiency* / Q000235:genetics; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D000199:Actins; D051242:Caveolin 1; D015638:Cytochalasin D; D003598:Cytoskeletal Proteins; D053538:Keratin-18; D053533:Keratin-8; D008565:Membrane Proteins; D019014:fas Receptor; D000099149:Ezrin; C486595:Krt8 protein, mouse; C106354:flotillins; C071776:radixin