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Infection and Immunity, November 2008, p. 5357-5365, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00221-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dynamin-2-Dependent Targeting of Mannheimia haemolytica Leukotoxin to Mitochondrial Cyclophilin D in Bovine Lymphoblastoid Cells{triangledown} ,{dagger}

Dhammika N. Atapattu,1 Ralph M. Albrecht,2 David J. McClenahan,1 and Charles J. Czuprynski1*

Department of Pathobiological Sciences, 2015 Linden Drive West, Madison, University of Wisconsin—Madison, Wisconsin 53706,1 Departments of Pediatrics and Animal Science, 1675 Observatory Drive, University of Wisconsin—Madison, Madison, Wisconsin 537062

Received 17 February 2008/ Returned for modification 9 June 2008/ Accepted 26 August 2008

Exotoxins which belong to the family containing the RTX toxins (repeats in toxin) contribute to a variety of important human and animal diseases. One example of such a toxin is the potent leukotoxin (LKT) produced by the bovine respiratory pathogen Mannheimia haemolytica. LKT binds to CD18, resulting in the death of bovine leukocytes. In this study, we showed that internalized LKT binds to the outer mitochondrial membrane, which results in the release of cytochrome c and collapse of the mitochondrial membrane potential ({psi}m). Incubation of bovine lymphoblastoid cells (BL-3 cells) with the mitochondrial membrane-stabilizing agent cyclosporine (CSA) reduced LKT-mediated cytotoxicity, cytochrome c release, and collapse of the {psi}m. Coimmunoprecipitation and intracellular binding studies suggested that LKT binds to the mitochondrial matrix protein cyclophilin D. We also demonstrated that LKT mobilizes the vesicle scission protein dynamin-2 from mitochondria to the cell membrane. Incubation with CSA depleted mitochondrial dynamin-2 in BL-3 cells, making it unavailable for vesicle scission and LKT internalization. The results of this study show that LKT trafficking and LKT-mediated cell death involve dynamin-2 and cyclophilin D, in a process that can be prevented by the mitochondrial membrane-protecting function of CSA.

* Corresponding author. Mailing address: Department of Pathobiological Sciences, 2015 Linden Drive West, University of Wisconsin—Madison, Madison, WI 53706. Phone and fax: (608) 262-8102. E-mail: czuprync{at}svm.vetmed.wisc.edu

{triangledown} Published ahead of print on 2 September 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: V. J. DiRita

Infection and Immunity, November 2008, p. 5357-5365, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00221-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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