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The Yersinia Effector Protein YpkA Induces Apoptosis Independently of Actin Depolymerization¹

Heiyoung Park^*,, Kabir Teja^*, John J. O’Shea^* and Richard M. Siegel^2,

^* Molecular Immunology and Inflammation Branch, and Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892

The pathogenicity of the plague agent Yersinia pestis is largely due to the injection of effector proteins that potently block immune responses into host cells through a type III secretion apparatus. One Yersinia effector protein, YpkA, a putative serine/threonine kinase, has been reported to act by depolymerizing actin and disrupting actin microfilament organization. Using YpkA-GFP fusion proteins to directly visualize cells expressing YpkA, we found instead that YpkA triggered rapid cell death that can be blocked by caspase inhibitors and Bcl-x_L, but was not dependent on caspase-8. The actin depolymerization promoted by YpkA was only seen in cells with other features of apoptosis, and was blocked by inhibiting apoptosis, indicating that actin filament disruption is likely to be a result, rather than a cause of YpkA-induced apoptosis. A region including aa 133–262 in YpkA was sufficient for inducing apoptosis independent of localization to the plasma membrane. These data suggest that YpkA can act as a direct inducer of cell death.

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.

¹ This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and by a National Institutes of Health-Food and Drug Administration trans-institute Intramural Biodefense grant from the National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Richard M. Siegel, Immunoregulation Unit, Autoimmunity Branch, Building 10 Room 9N238, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892. E-mail address: rsiegel{at}nih.gov

³ Abbreviations used in this paper: YOP, Yersinia outer protein; MDM, monocyte-derived macrophage; TTSS, type III secretion system; TMRM, tetramethylrhodamine methyl; FADD, Fas-associated death domain; YFP, yellow fluorescent protein; CFP, cyan fluorescent protein.