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A more recent version of this article appeared on July 1, 2006
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Submitted on December 5, 2005
Accepted on April 24, 2006
*Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905; Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Sphingolipids (SLs) play important roles in membrane structure and cell function. Here we examine the SL requirements of various endocytic mechanisms using a mutant cell line and pharmacological inhibitors to disrupt SL biosynthesis. First, we demonstrated that in CHO cells we could distinguish three distinct mechanisms of clathrin-independent endocytosis (caveolar, RhoA- and cdc42-dependent) which differed in cargo, sensitivity to pharmacologic agents and dominant negative proteins. General depletion of SLs inhibited endocytosis by each clathrin-independent mechanism, while clathrin-dependent uptake was unaffected. Depletion of glycosphingolipids (GSLs; a subgroup of SLs) selectively blocked caveolar endocytosis, and decreased caveolin-1 and caveolae at the plasma membrane. Caveolar endocytosis and PM caveolae could be restored in GSL-depleted cells by acute addition of exogenous GSLs. Disruption of RhoA- and Cdc42-regulated endocytosis by SL depletion was shown to be related to decreased targeting of these Rho proteins to the plasma membrane and could be partially restored by exogenous sphingomyelin but not GSLs. Both the in vivo membrane targeting and in vitro binding to artificial lipid vesicles of RhoA and Cdc42 were shown to be dependent upon sphingomyelin. These results provide the first evidence that SLs are differentially required for distinct mechanisms of clathrin-independent endocytosis.
Present address: Photometrics, 3440 East Britannia Drive, Tucson, AZ 85706.
Address correspondence to:
Richard E. Pagano (pagano.richard{at}mayo.edu)
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