Glycosphingolipid Mediated Caveolin-1 Oligomerization.

Abstract

We have previously demonstrated an association between the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) and the loss of high molecular weight oligomers in the aortas of α-galactosidase A-knockout mice, a model of Fabry disease. In the present study the molecular basis for the association between glycosphingolipids and caveolin-1 oligomerization was further investigated. Cellular glycosphingolipids were selectively depleted by treatment with a series of sphingolipid synthesis inhibitors, including D-threo-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol, fumonisin B1 and myriocin. The depletion of glycosphingolipids resulted in the loss of high molecular mass oligomers of caveolin-1 in plasma membranes of cultured ECV-304 cells as well as in the caveolar fractions of Hela cells as measured by immunoblotting. The disruption of caveolin-1 high molecular weight oligomer formation caused by changes of composition of glycosphingolipids may be directly involved in the interruption of cellular functions including caveolar stabilization, membrane trafficking and signal transduction. These results suggest a specific role for glycosphingolipidsin the caveolar co-localization and oligomerization of caveolin-1.