Abstract
Gaucher disease is a lysosomal storage disease characterized by the malfunction of glucocerebrosidase resulting in the accumulation of glucosylceramide and other sphingolipids in certain cells. Although the disease symptoms are usually attributed to the storage of undigested substrate in lysosomes, here we show that glycosphingolipids accumulating in the plasma membrane cause profound changes in the properties of the membrane. The fluidity of the sphingolipid-enriched membrane decreased accompanied by the enlargement of raft-like ordered membrane domains. The mobility of non-raft proteins and lipids was severely restricted, while raft-resident components were only mildly affected. The rate of endocytosis of transferrin receptor, a non-raft protein, was significantly retarded in Gaucher cells, while the endocytosis of the raft-associated GM1 ganglioside was unaffected. Interferon-γ-induced STAT1 phosphorylation was also significantly inhibited in Gaucher cells. Atomic force microscopy revealed that sphingolipid accumulation was associated with a more compliant membrane capable of producing an increased number of nanotubes. The results imply that glycosphingolipid accumulation in the plasma membrane has significant effects on membrane properties, which may be important in the pathogenesis of Gaucher disease.
Highlights
The plasma membrane constitutes an interface between the cell and its surroundings, and it is the site of numerous transmembrane signaling and membrane trafficking events
Treatment with conduritol B epoxide (CBE), an inhibitor of glucocerebrosidase, was used to induce the Gaucher phenotype in vitro[7,9]. This chemically induced model of the disease has been used extensively for the characterization of disease symptoms and cellular changes associated with sphingolipid accumulation, and the CBE-induced and knock-out models of Gaucher disease show remarkably similarities with regard to pathological features and gene expression profile[17,18]
CBE may inhibit the activity of non-lysosomal β-glucosidase (GBA2) as well[19], this effect results in glycosphingolipid accumulation supporting the appropriateness of the model system for studying the consequences of glycosphingolipid accumulation[20]
Summary
The plasma membrane constitutes an interface between the cell and its surroundings, and it is the site of numerous transmembrane signaling and membrane trafficking events. Increased concentration of these lipids have been observed in the plasma membrane in in vitro and in vivo models[7,8,9] Such alterations in the composition of the plasma membrane are expected to change its biophysical and cell biological properties. The nature and even the existence of lipid rafts are fiercely contested They are generally believed to be cholesterol- and sphingolipid-enriched microdomains with submicroscopic size thought to correspond to liquid-ordered domains observed in artificial membranes[10,11,12]. According to a reasonable compromise between the conflicting views lipid rafts may be envisaged as submicroscopic, highly dynamic microdomains enriched in cholesterol, sphingolipids and certain proteins whose existence is not primarily caused by lipid partitioning, but by protein-lipid interactions, membrane trafficking and interactions of the membrane with the cytoskeleton[15,16]
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