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Geranylgeranylation but not GTP loading determines rho migratory function in T cells

Item Type:Article
Title:Geranylgeranylation but not GTP loading determines rho migratory function in T cells
Creators Name:Waiczies, S. and Bendix, I. and Prozorovski, T. and Ratner, M. and Nazarenko, I. and Pfueller, C.F. and Brandt, A.U. and Herz, J. and Brocke, S. and Ullrich, O. and Zipp, F.
Abstract: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.
Keywords:Apoptosis, Brain, Caspase 3, Cell Line, Cell Movement, Cytoskeleton, Cytosol, Enzyme Activation, Guanosine Triphosphate, Phenalenes, Polyisoprenyl Phosphates, Prenylation, Protein Binding, rho-Associated Kinases, rhoA GTP-Binding Protein, T-Lymphocytes, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:179
Number:9
Page Range:6024-6032
Date:1 November 2007
Official Publication:http://www.jimmunol.org/cgi/content/abstract/179/9/6024
PubMed:View item in PubMed

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