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Published online March 19, 2007
doi:10.1083/jcb.200609149
The Journal of Cell Biology, Vol. 176, No. 7, 895-901
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Singh et al.
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Inhibition of caveolar uptake, SV40 infection, and ß1-integrin signaling by a nonnatural glycosphingolipid stereoisomer



Raman Deep Singh1, Eileen L. Holicky1, Zhi-jie Cheng1, Seong-Youl Kim1, Christine L. Wheatley1, David L. Marks1, Robert Bittman2, and Richard E. Pagano1

1 Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, Mayo Clinic College of Medicine, Rochester, MN 55905
2 Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, NY 11367

Correspondence to Richard E. Pagano: pagano.richard{at}mayo.edu

Caveolar endocytosis is an important mechanism for the uptake of certain pathogens and toxins and also plays a role in the internalization of some plasma membrane (PM) lipids and proteins. However, the regulation of caveolar endocytosis is not well understood. We previously demonstrated that caveolar endocytosis and ß1-integrin signaling are stimulated by exogenous glycosphingolipids (GSLs). In this study, we show that a synthetic GSL with nonnatural stereochemistry, ß-D-lactosyl-N-octanoyl-L-threo-sphingosine, (1) selectively inhibits caveolar endocytosis and SV40 virus infection, (2) blocks the clustering of lipids and proteins into GSLs and cholesterol-enriched microdomains (rafts) at the PM, and (3) inhibits ß1-integrin activation and downstream signaling. Finally, we show that small interfering RNA knockdown of ß1 integrin in human skin fibroblasts blocks caveolar endocytosis and the stimulation of signaling by a GSL with natural stereochemistry. These experiments identify a new compound that can interfere with biological processes by inhibiting microdomain formation and also identify ß1 integrin as a potential mediator of signaling by GSLs.

Abbreviations used in this paper: Ab, antibody; ß1-stim Ab, stimulatory ß1-integrin Ab; CtxB, cholera toxin B; GPI, glycosyl-phosphatidylinositol; GSL, glycosphingolipid; HSF, human skin fibroblast; IL-2R, interleukin-2 receptor ß subunit; LacCer, lactosylceramide; PM, plasma membrane; Tfn, transferrin.


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