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Infect Immun, June 1998, p. 2607-2613, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Modification of Ras in Eukaryotic Cells by Pseudomonas aeruginosa Exoenzyme S

Eileen M. McGuffie,1 Dara W. Frank,2 Timothy S. Vincent,1 and Joan C. Olson1,*

Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425,1 and Department of Microbiology, Medical College of Wisconsin, Milwaukee, Wisconsin 532262

Received 4 December 1997/Returned for modification 20 February 1998/Accepted 31 March 1998

Genetic and functional data suggest that Pseudomonas aeruginosa exoenzyme S (ExoS), an ADP-ribosyltransferase, is translocated into eukaryotic cells by a bacterial type III secretory mechanism activated by contact between bacteria and host cells. Although purified ExoS is not toxic to eukaryotic cells, ExoS-producing bacteria cause reduced proliferation and viability, possibly mediated by bacterially translocated ExoS. To investigate the activity of translocated ExoS, we examined in vivo modification of Ras, a preferred in vitro substrate. The ExoS-producing strain P. aeruginosa 388 and an isogenic mutant strain, 388Delta exoS, which fails to produce ExoS, were cocultured with HT29 colon carcinoma cells. Ras was found to be ADP-ribosylated during coculture with 388 but not with 388Delta exoS, and Ras modification by 388 corresponded with reduction in HT29 cell DNA synthesis. Active translocation by bacteria was found to be required, since exogenous ExoS, alone or in the presence of 388Delta exoS, was unable to modify intracellular Ras. Other ExoS-producing strains caused modification of Ras, indicating that this is not a strain-specific event. ADP-ribosylation of Rap1, an additional Ras family substrate for ExoS in vitro, was not detectable in vivo under conditions sufficient for Ras modification, suggesting possible ExoS substrate preference among Ras-related proteins. These results confirm that intracellular Ras is modified by bacterially translocated ExoS and that the inhibition of target cell proliferation correlates with the efficiency of Ras modification.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425. Phone: (803) 792-7761. Fax: (803) 792-4157. E-mail: olsonj{at}musc.edu.

Infect Immun, June 1998, p. 2607-2613, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.