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J. Biol. Chem., Vol. 280, Issue 10, 9058-9064, March 11, 2005

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The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt^*

Leigh A. Knodler, B. Brett Finlay¶, and Olivia Steele-Mortimer||

From the Laboratory of Intracellular Parasites, NIAID, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana 59840 and the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada

Invasion of epithelial cells by Salmonella enterica is mediated by bacterial "effector" proteins that are delivered into the host cell by a type III secretion system. Although primarily known for their roles in actin rearrangements and membrane ruffling, translocated effectors also affect host cell processes that are not directly associated with invasion. Here, we show that SopB/SigD, an effector with phosphoinositide phosphatase activity, has anti-apoptotic activity in Salmonella-infected epithelial cells. Salmonella induced the sustained activation of Akt/protein kinase B, a pro-survival kinase, in a SopB-dependent manner. Failure to activate Akt resulted in increased levels of apoptosis after infection with a sopB deletion mutant (sopB). Furthermore, cells infected with wild type bacteria, but not the sopB strain, were protected from camptothecin-induced cleavage of caspase-3 and subsequent apoptosis. The anti-apoptotic activity of SopB was dependent on its phosphatase activity, because a catalytically inactive mutant was unable to protect cells from the effects of camptothecin. Finally, small interfering RNA was used to demonstrate the essential role of Akt in SopB-mediated protection against apoptosis. These results provide new insights into the mechanisms of apoptosis and highlight how bacterial effectors can intercept signaling pathways to manipulate host responses.

Received for publication, November 8, 2004 , and in revised form, December 29, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the Howard Hughes Medical Institute and the Canadian Institute of Health Research.

^|| To whom correspondence should be addressed: Rocky Mountain Laboratories, 903 South 4th St., Hamilton, MT 59840. Tel.: 406-363-9292; Fax: 406-363-9380; E-mail: omortimer{at}niaid.nih.gov.

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