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.

Intact glycosphingolipidomic analysis of the cell membrane during differentiation yields extensive glycan and lipid changes

“…A study of gangliosides from human serum using nano-HPLC-ESI Q-TOF MS also by Kirsch et al . profiled 33 gangliosides and yielded potential biomarkers for pancreatic cancer, illustrating the potential of profiling methods for biomarker discovery 34 .…”

3-Nitrotyrosine as a biomarker for vascular involvement in Fabry disease

“…In 2000, Leon Fine and colleagues suggested that chronic kidney hypoxia might be a phenotypic characteristic of models of kidneys with decreased surviving nephrons. 3 During the past decade, several studies of experimental animal models of CKD and the diabetic kidney have verified the earlier prediction that kidney hypoxia does persist in both CKD [4][5][6] and the early diabetic kidney (Figure 1). 7 Why should hypoxia develop as a primary characteristic of or adaptation to CKD and the diabetic kidney?…”

“…7 Why should hypoxia develop as a primary characteristic of or adaptation to CKD and the diabetic kidney? Early studies in the subtotal nephrectomy model demonstrated that peritubular capillary rarefaction does occur, 5 raising the question of whether the hypoxia was primarily ischemic in origin. However, this seems less likely given the anatomic arrangement of arterial and venous vessels in the kidney.…”

“…Glycosphingolipid accumulation is not restricted to the lysosome but is also increased in the plasma membranes and caveolae of endothelial cells. Such accumulation may compromise caveolar stability, 5 and the downstream signal transduction of caveolar resident proteins, including eNOS ( Figure 1).…”

Gene Signature of Human Oral Mucosa Fibroblasts: Comparison with Dermal Fibroblasts and Induced Pluripotent Stem Cells

“…Lower expression of B3GALT5 may cause the accumulation of Gb4cer or globotriaosylceramide (Gb3cer). Because Gb3cer and other glycosphingolipids are also involved in caveolar-1 oligomerization [ 39 ], their accumulation may affect the sorting and trafficking of caveolae in the membrane, resulting in the function of signaling in fibroblasts. Taken together, the expression profiles of GSLs-GTs suggested their possible roles in “the environmental sensor” in fibroblasts through membrane metabolism.…”