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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., Bendix, I., Prozorovski, T., Ratner, M., Nazarenko, I., Pfueller, C.F., Brandt, A.U., Herz, J., Brocke, S., 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
Publisher:American Association of Immunologists
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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