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Infection and Immunity, July 2008, p. 3293-3303, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00365-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cholesterol Depletion Reduces Helicobacter pylori CagA Translocation and CagA-Induced Responses in AGS Cells{triangledown}

Chih-Ho Lai,1,2 Yun-Chieh Chang,1 Shin-Yi Du,1 Hung-Jung Wang,1 Chun-Hsien Kuo,1 Shih-Hua Fang,3 Hua-Wen Fu,1 Hui-Hao Lin,4 Ann-Shyn Chiang,4 and Wen-Ching Wang1*

Institute of Molecular and Cellular Biology & Department of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan,1 Department of Microbiology, China Medical University, Taichung, Taiwan,2 Institute of Athletes, National Taiwan Sport University, Taipei, Taiwan,3 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan4

Received 20 March 2008/ Accepted 19 April 2008

Infection with Helicobacter pylori cagA-positive strains is associated with gastritis, ulcerations, and gastric cancer. CagA is translocated into infected epithelial cells by a type IV secretion system and can be tyrosine phosphorylated, inducing signal transduction and motogenic responses in epithelial cells. Cellular cholesterol, a vital component of the membrane, contributes to membrane dynamics and functions and is important in VacA intoxication and phagocyte evasion during H. pylori infection. In this investigation, we showed that cholesterol extraction by methyl-β-cyclodextrin reduced the level of CagA translocation and phosphorylation. Confocal microscope visualization revealed that a significant portion of translocated CagA was colocalized with the raft marker GM1 and c-Src during infection. Moreover, GM1 was rapidly recruited into sites of bacterial attachment by live-cell imaging analysis. CagA and VacA were cofractionated with detergent-resistant membranes (DRMs), suggesting that the distribution of CagA and VacA is associated with rafts in infected cells. Upon cholesterol depletion, the distribution shifted to non-DRMs. Accordingly, the CagA-induced hummingbird phenotype and interleukin-8 induction were blocked by cholesterol depletion. Raft-disrupting agents did not influence bacterial adherence but did significantly reduce internalization activity in AGS cells. Together, these results suggest that delivery of CagA into epithelial cells by the bacterial type IV secretion system is mediated in a cholesterol-dependent manner.

* Corresponding author. Mailing address: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 300. Phone: 886-3-5742766. Fax: 886-3-5742766. E-mail: wcwang{at}life.nthu.edu.tw

{triangledown} Published ahead of print on 28 April 2008.

Editor: J. B. Bliska

Infection and Immunity, July 2008, p. 3293-3303, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00365-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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