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Journal of Bacteriology, October 2006, p. 7049-7061, Vol. 188, No. 20
0021-9193/06/$08.00+0     doi:10.1128/JB.00688-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Bactericidal Activity of both Secreted and Nonsecreted Microcin E492 Requires the Mannose Permease

Sylvain Bieler,^1,2,3 Filo Silva,¹ Claudio Soto,³ and Dominique Belin^1*

Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland,¹ Department of Cell Biology, University of Geneva, Geneva, Switzerland,² Department of Neurology, University of Texas Medical Branch, Galveston, Texas,^{3 3}

Received 15 May 2006/ Accepted 24 June 2006

Microcin E492 (MccE492) is a bactericidal protein secreted by Klebsiella pneumoniae that is active against various species of Enterobacteriaceae. Interaction of MccE492 with target cells leads to the depolarization and permeabilization of their inner membranes. Several MccE492-specific proteins are required for the maturation and secretion of active MccE492. Surprisingly, the expression of only MceA, the polypeptide backbone of MccE492, is shown here to be toxic by itself. We refer to this phenomenon as endogenous MceA bactericidal activity to differentiate it from the action of extracellularly secreted MccE492. The toxicity of endogenous MceA is enhanced by an efficient targeting to the inner membrane. However, a periplasmic intermediate state is not required for MceA toxicity. Indeed, endogenous MceA remains fully active when it is fused to thioredoxin-1, a fast-folding protein that promotes retention of the C terminus of MceA in the cytoplasm. The C-terminal domain of MccE492 is required only for delivery from the extracellular environment to the periplasm, and it is not required for inner membrane damage. A common component is absolutely essential for the bactericidal activity of both endogenous MceA and extracellular MccE492. Indeed, toxicity is strictly dependent on the presence of ManYZ, an inner membrane protein complex involved in mannose uptake. Based on these findings, we propose a new model for cell entry, inner membrane insertion, and toxic activity of MccE492.

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* Corresponding author. Mailing address: Department of Pathology and Immunology, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. Phone: 41 22 3795769. Fax: 41 22 3795746. E-mail: dominique.belin{at}medecine.unige.ch.

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Journal of Bacteriology, October 2006, p. 7049-7061, Vol. 188, No. 20
0021-9193/06/$08.00+0     doi:10.1128/JB.00688-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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