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Infection and Immunity, August 2002, p. 4112-4123, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4112-4123.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Plasma Membrane Cholesterol Modulates Cellular Vacuolation Induced by the Helicobacter pylori Vacuolating Cytotoxin

Hetal K. Patel, David C. Willhite, Rakhi M. Patel, Dan Ye, Christopher L. Williams, Eric M. Torres, Kent B. Marty, Robert A. MacDonald, and Steven R. Blanke*

Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001

Received 20 March 2002/ Accepted 29 April 2002

The Helicobacter pylori vacuolating cytotoxin (VacA) induces the degenerative vacuolation of mammalian cells both in vitro and in vivo. Here, we demonstrate that plasma membrane cholesterol is essential for vacuolation of mammalian cells by VacA. Vacuole biogenesis in multiple cell lines was completely blocked when cholesterol was extracted selectively from the plasma membrane by using ß-cyclodextrins. Moreover, increasing plasma membrane cholesterol levels strongly potentiated VacA-induced vacuolation. In contrast, inhibiting de novo biosynthesis of cholesterol with lovastatin or compactin had no detectable effect on vacuolation. While depletion of plasma membrane cholesterol has been shown to interfere with both clathrin-mediated endocytosis and caveola-dependent endocytosis, neither of these two internalization pathways was found to be essential for vacuolation of cells by VacA. Depleting plasma membrane cholesterol attenuated the entry of VacA into HeLa cells. In addition, ß-cyclodextrin reagents blocked vacuolation of cells that were either preloaded with VacA or had VacA directly expressed within the cytosol. Collectively, our results suggest that plasma membrane cholesterol is important for both the intoxication mechanism of VacA and subsequent vacuole biogenesis.

* Corresponding author. Mailing address: Department of Biology and Biochemistry, University of Houston, 369 Science and Research Bldg. II, Houston, TX 77204-5001. Phone: (713) 743-8392. Fax: (713) 743-8351. E-mail: sblanke{at}uh.edu.

Editor: J. T. Barbieri

Infection and Immunity, August 2002, p. 4112-4123, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4112-4123.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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