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J. Biol. Chem., Vol. 280, Issue 15, 14620-14627, April 15, 2005

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A Salmonella typhimurium Effector Protein SifA Is Modified by Host Cell Prenylation and S-Acylation Machinery^*

Anna T. Reinicke, James L. Hutchinson, Anthony I. Magee¶, Piero Mastroeni||, John Trowsdale, and Adrian P. Kelly**

From the Division of Immunology, Department of Pathology and the ^||Bacterial Infection Group, Department of Clinical Veterinary Medicine, Center for Veterinary Science, University of Cambridge, Cambridge CB2 1QP, United Kingdom and the ^¶Division of Biomedical Sciences, Imperial College, London SW7 2AZ, United Kingdom

SifA is a Salmonella effector protein that is required for maintenance of the vacuolar membrane that surrounds replicating bacteria. It associates with the Salmonella-containing vacuole but how it interacts with the membrane is unknown. Here we show by immunofluorescence, S100 fractionation and Triton X-114 partitioning that the membrane association and targeting properties of SifA are influenced by a motif encoded within the C-terminal six amino acids. This sequence shares homology with both CAAX and Rab geranylgeranyl transferase prenylation motifs. We characterized the post-translational processing of SifA and showed that the cysteine residue within the CAAX motif is modified by isoprenoid addition through the action of protein geranylgeranyl transferase I. SifA was additionally modified by S-acylation of an adjacent cysteine residue. Similar modifications to host cell proteins regulate numerous functions including protein targeting, membrane association, protein-protein interaction, and signal transduction. This is the only known example of a bacterial effector protein that is modified both by mammalian cell S-acylation and prenylation machinery.

Received for publication, January 4, 2005 , and in revised form, February 14, 2005.

^* This work was supported by funding from the Medical Research Council (MRC), The Wellcome Trust, and Marie Curie EU Network Number MRTN-CT-2003-504227. 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 an MRC studentship.

^** To whom correspondence should be addressed: Division of Immunology, Dept. of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. Tel.: 44-1223-333591; Fax: 44-1223-339768; E-mail: apk23{at}mole.bio.cam.ac.uk.

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