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* Zentrum für Infektionsforschung, Universität Würzburg, Würzburg, Germany;
Universität Ulm, Abteilung Physiologische Chemie, Ulm, Germany;
Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany; and
Universität Konstanz, Lehrstuhl Zellbiologie, Konstanz, Germany
The human granulocyte-specific receptor carcinoembryonic antigen-related cell adhesion molecule (CEACAM)3 is critically involved in the opsonin-independent recognition of several bacterial pathogens. CEACAM3-mediated phagocytosis depends on the integrity of an ITAM-like sequence within the cytoplasmic domain of CEACAM3 and is characterized by rapid stimulation of the GTPase Rac. By performing a functional screen with CEACAM3-expressing cells, we found that overexpression of a dominant-negative form of the guanine nucleotide exchange factor Vav, but not the dominant-negative versions SWAP70, Dock2, or ELMO1 interfered with CEACAM3-initiated phagocytosis. Moreover, small interfering RNA-mediated silencing of Vav reduced uptake and abrogated the stimulation of Rac in response to bacterial CEACAM3 engagement. In Vav1/Vav2-deficient cells, CEACAM3-mediated internalization was only observed after re-expression of Vav. Vav colocalized with CEACAM3 upon bacterial infection, coimmunoprecipitated in a complex with CEACAM3, and the Vav Src homology 2 domain directly associated with phosphorylated Tyr230 of CEACAM3. In primary human granulocytes, TAT-mediated transduction of dominant-negative Vav, but not SWAP70, severely impaired the uptake of CEACAM3-binding bacteria. These data support the view that, different from canonical ITAM signaling, the CEACAM3 ITAM-like sequence short-wires bacterial recognition and Rac stimulation via a direct association with Vav to promote rapid phagocytosis and elimination of CEACAM-binding human pathogens.
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1 This work was supported by Ha2568/3-2 funds from the DFG (to C.R.H.).
2 Current address: ACE BioSciences, Unsbjergvej 2A, 5220 Odense, Denmark.
3 Address correspondence and reprint requests to Dr. Christof R. Hauck, Universität Konstanz, Lehrstuhl Zellbiologie, Maildrop X908, 78457 Konstanz, Germany. E-mail address: christof.hauck{at}uni-konstanz.de
4 Abbreviations used in this paper: Opa, opacity-associated; dn, dominant negative; GEF, guanine nucleotide exchange factor; PTK, protein tyrosine kinase; RFP, red fluorescent protein; HA, hemagglutinin; SH2, Src homology 2; CEACAM, carcinoembryonic antigen-related cell adhesion molecule; siRNA, small interfering RNA; WT, wild type.
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  T. Schmitter, S. Pils, S. Weibel, F. Agerer, L. Peterson, A. Buntru, K. Kopp, and C. R. Hauck Opa Proteins of Pathogenic Neisseriae Initiate Src Kinase-Dependent or Lipid Raft-Mediated Uptake via Distinct Human Carcinoembryonic Antigen-Related Cell Adhesion Molecule Isoforms Infect. Immun., August 1, 2007; 75(8): 4116 - 4126. [Abstract] [Full Text] [PDF]
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