Keratin impact on PKCδ/ASMase regulation of hepatocyte lipid raft size: Implication in FasR-associated apoptosis

Abstract

Keratins are epithelial cell intermediate filament proteins (IFs) that are expressed as pairs in a cell differentiation-regulated manner. Hepatocytes express keratin 8 (K8)/18 (K18) IFs, and a loss of K8 or K18, as in K8-null mice, leads to degradation of the keratin partner. We previously reported that a K8/K18 loss in hepatocytes leads to altered cell surface lipid raft distribution and more efficient Fas receptor (FasR)-mediated apoptosis. We demonstrate here that absence of K8 or transgenic expression of the K8 G62C mutant in mouse hepatocytes reduces lipid raft size. Mechanistically, we find that the lipid raft size is dependent on acid sphingomyelinase (ASMase) enzyme activity, which is reduced in absence of K8/K18. Notably, reduction of ASMase activity reduction parallels less efficient redistribution surface membrane PKCδ toward lysosomes. Moreover, we delineate the lipid raft volume range that is required for an optimal FasR-mediated apoptosis. Hence, K8/K18-dependent PKCδ/ASMase modulation of lipid raft size can explain the more prominent FasR-mediated signalling resulting from K8/K18 loss. The ASMase fine-tuning regulation of lipid rafts may provide a therapeutic target for death receptor-related liver diseases.