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* Cecilie-Vogt-Clinic for Molecular Neurology, Charité–University Medicine and Max Delbruck Center for Molecular Medicine, Berlin, Germany;
Experimental Pathology, Department of Pathology, Hadassah Medical School, Jerusalem, Israel;
Institute of Pathology, Charité–University Medicine, Berlin, Germany;
Cellular and Molecular Pharmacology, University of Connecticut Health Center Farmington, CT 06030; and
¶ Institute of Anatomy, University of Zurich, Zurich, Switzerland
Rho GTPases orchestrate signaling pathways leading to cell migration. Their function depends on GTP loading and isoprenylation by geranylgeranyl pyrophosphate (GGpp). In this study, we show that in human T cells, geranylgeranylation—and not GTP loading—is necessary for RhoA-mediated downstream events. As a result of GGpp depletion with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin, RhoA was sequestered from the membrane to the cytosol and, notwithstanding increased GTP loading, the constitutive activation of its substrate Rho-associated coiled-coil protein kinase-1 was blocked. In line with this, T cells expressing increased GTP-RhoA failed to form an intact cytoskeleton and to migrate toward a chemokine gradient. In vivo treatment with atorvastatin in the rodent model of multiple sclerosis markedly decreased the capacity of activated T cells to traffic within the brain, as demonstrated by multiphoton analysis. Thus, tethering of RhoA to the membrane by GGpp is determinant for T cell migration and provides a mechanism for preventing T cell infiltration into inflamed compartments by 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors,
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1 This work was supported by grants from Charité (to S.W.; Habilitationsprojekt 2006-202a), and from the Federal Ministry of Education and Research (German Israeli Cooperation) and the German Research Foundation (Deutsche Forschungsgemeinschaft: Sonderforschungsbereich 650) to F.Z.
2 S.W. and I.B. contributed equally.
3 Address correspondence and reprint requests to Dr. Frauke Zipp, Cecilie-Vogt-Clinic for Molecular Neurology, Charité–University Medicine and Max Delbrueck Center for Molecular Medicine, Charitéplatz 1, 10117 Berlin, Germany. E-mail address: frauke.zipp{at}charite.de
4 Abbreviations used in this paper: ROCK1, Rho-associated coiled-coil protein kinase 1; RBD, Rho-binding domain; GGpp, geranylgeranyl pyrophosphate; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HMGCRI, HMG-CoA reductase inhibitor; PLP, proteolipid protein; NP40, Nonidet P40; 7-AAD, 7-aminoactinomycin D; RT, room temperature; MFI, mean fluorescence intensity; PB, peripheral blood; MLC, myosin L chain; RIPA, radioimmunoprecipitation assay.
5 The online version of this article contains supplemental material.
This article has been cited by other articles:
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  S. Waiczies, I. Bendix, and F. Zipp Geranylgeranylation but Not GTP-Loading of Rho GTPases Determines T Cell Function Sci. Signal., March 25, 2008; 1(12): pt3 - pt3. [Abstract] [Full Text] [PDF]
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