Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation

Keratins 8 and 18 belong to the keratin family of intermediate filament (IF ) proteins and constitute a hallmark for all simple epithelia, including th e liver. Hepatocyte IFs are made solely of keratins 8 and 18 (K8/K18). In t hese cells, the loss of one partner via a targeted null mutation in the ger mline results in hepatocytes lacking K8/K18 IFs, thus providing a model of choice for examining the function(s) of simple epithelium keratins. Here, w e report that K8-null mouse hepatocytes in primary culture and in vivo are three- to fourfold more sensitive than wildtype (WT) mouse hepatocytes to F as-mediated apoptosis after stimulation with Jot, an agonistic antibody of Fas ligand. This increased sensitivity is associated with a higher and more rapid caspase-3 activation and DNA fragmentation. In contrast, no differen ce in apoptosis is observed between cultured K8-null and WT hepatocytes aft er addition of the Fas-related death-factors tumor necrosis factor (TNF) al pha or TNF-related apoptosis-inducing ligand. Analyses of the Fas distribut ion in K8-null and WT hepatocytes in culture and in situ demonstrate a more prominent targeting of the receptor to the surface membrane of K8-null hep atocytes. Moreover, altering Fas trafficking by disrupting microtubules wit h colchicine reduces by twofold the protection generated against Jot-induce d lethal action in K8-null versus WT hepatocytes. Together, the results str ongly suggest that simple epithelium K8/K18 provide resistance to Fas-media ted apoptosis and that this protection occurs through a modulation of Fas t argeting to the cell surface.