The medium is the message: Glycosphingolipids and their soluble analogues

Abstract

We have made adamantylGSLs by substituting the fatty acids of primarily, globotriaosyl ceramide(Gb 3) and sulfogalactosyl ceramide(SGC), with the rigid α-adamantane hydrocarbon frame. These analogues have proven to be remarkably water-soluble but retain the receptor function of the parent membrane GSL. AdaGb 3 prevents the binding of verotoxins to target cells but increased pathology in vivo, likely due to the partitioning into receptor negative target cells to provide pseudo-receptors. Preincubation of HIV with adaGb 3 prevents cellular infection in vitro and viral-host cell fusion. Cellular accumulation of Gb 3 reduces HIV susceptibility in vitro, whereas lack of Gb 3 promotes infection, suggesting that Gb 3 expression could be a novel risk factor for HIV susceptibility. AdaGb 3 has proven to be a new inhibitor for the MDR1 drug pump (P-glycoprotein) and can reverse drug resistance in cell culture. AdaSGC is bound by hsp70/hsc70 within the N-terminal ATPase domain and inhibits chaperone function. When added to cells transfected with the ΔF508 CFTR mutant, adaSGC was able to decrease ER degradation of this mutant protein, an hsc70 dependent process. Our finding that ΔF508 CFTR expressing cells show reduced SGC biosynthesis suggests that SGC could be an additional natural regulator of the hsp70 chaperone ATPase cycle.