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Infection and Immunity, June 2008, p. 2715-2721, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.00153-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase Activation by Neisseria gonorrhoeae Downregulates Epithelial Cell Proapoptotic Proteins Bad and Bim{triangledown}

Heather L. Howie,{dagger} Shelly L. Shiflett,{ddagger} and Magdalene So*

Department of Molecular Microbiology & Immunology, L220, Oregon Health and Science University, Portland, Oregon 97201

Received 5 February 2008/ Returned for modification 27 February 2008/ Accepted 26 March 2008

Neisseria gonorrhoeae expressing type IV pili (Tfp) activates extracellular signal-regulated kinase (ERK) and induces a cytoprotective state in the epithelial cell in a manner that is enhanced by pilT. As the ERK signaling pathway is well-known for its role in cytoprotection and cell survival, we tested the hypothesis that ERK is involved in producing this cytoprotective effect. Inhibiting ERK activation prior to infection attenuated the ability of these bacteria to induce cytoprotection. Activated ERK specifically targeted two proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins, Bim and Bad, for downregulation at the protein level. Bim downregulation occurred through the proteasome. ERK, in addition, inactivated Bad by triggering its phosphorylation at Ser112. Finally, reducing the level of either Bad or Bim alone by small interfering RNA was sufficient to protect uninfected cells from staurosporine-induced apoptosis. We conclude that Tfp-induced cytoprotection is due in part to ERK-dependent modification and/or downregulation of proapoptotic proteins Bad and Bim.

* Corresponding author. Present address: Department of Immunobiology and BIO5 Institute, University of Arizona, 1657 E. Helen St., Keating 224, Tucson, AZ 85721. Phone: (520) 626-3097. Fax: (520) 626-4824. E-mail: somaggie{at}email.arizona.edu

{triangledown} Published ahead of print on 7 April 2008.

Editor: J. N. Weiser

{dagger} Present address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109.

{ddagger} Present address: Idaho Technologies, 390 Wakara Way, Salt Lake City, UT 84108.

Infection and Immunity, June 2008, p. 2715-2721, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.00153-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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