The ERM protein, ezrin, regulates neutrophil transmigration by modulating the apical localization of MRP2 in response to the SipA effector protein during Salmonella Typhimurium infection.

Abstract

In human disease induced by Salmonella enterica serovar Typhimurium (S. Typhimurium), transepithelial migration of neutrophils rapidly follows attachment of the bacteria to the epithelial apical membrane. We have previously shown that during S. Typhimurium infection the multidrug resistance-associated protein 2 (MRP2) is highly expressed at the apical surface of the intestinal epithelia, and that it functions as an efflux pump for the potent neutrophil chemoattractant hepoxilin A(3) . However, the molecular mechanisms regulating its apical localization during active states of inflammation remain unknown. Thus, our objective was to determine the mechanistic basis for the translocation of MRP2 to the apical surface of intestinal epithelial cells during S. Typhimurium infection. We show that suppression of ezrin, through either RNAi or truncation of the C-terminus, results not only in a decrease in S. Typhimurium-induced neutrophil transmigration but also significantly attenuates the apical membrane expression of MRP2 during Salmonella infection. In addition, we determined that S. Typhimurium induces the activation of ezrin via a PKC-α-dependent pathway and that ezrin activation is coupled to apical localization of MRP2. Based on these results we propose that activation of ezrin is required for the apical localization of MRP2 during S. Typhimurium infection.

• Authors: Terence A Agbor, Zachary C Demma, Karen L Mumy, Jeffrey D Bien, Beth A McCormick
• Journal: Cellular microbiology (Cell Microbiol) Vol. 13 Issue 12 Pg. 2007-21 (Dec 2011) ISSN: 1462-5822 [Electronic] India
• PMID: 21899702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Blackwell Publishing Ltd.

Chemical References

• ABCC2 protein, human
• Bacterial Proteins
• Benzophenanthridines
• Carbazoles
• Cytoskeletal Proteins
• Microfilament Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• RNA, Small Interfering
• SipA protein, Salmonella
• ezrin
• Go 6976
• chelerythrine
• Protein Kinase C-alpha

Topics

• Bacterial Proteins (genetics, metabolism)
• Benzophenanthridines (pharmacology)
• Blotting, Western
• Carbazoles (pharmacology)
• Cell Line, Tumor
• Cell Movement
• Cytoskeletal Proteins (genetics, metabolism)
• Humans
• Intestinal Mucosa (metabolism, microbiology)
• Microfilament Proteins (genetics, metabolism)
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Neutrophils (metabolism)
• Phosphorylation
• Protein Kinase C-alpha (genetics, metabolism)
• Protein Transport
• RNA, Small Interfering (genetics, metabolism)
• Salmonella Infections (metabolism, microbiology)
• Salmonella typhimurium (drug effects, genetics, metabolism, pathogenicity)
• Transfection