Geranylgeranylation but not GTP loading determines rho migratory function in T cells.
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.
Waiczies
Sonia
S
Cecilie-Vogt-Clinic for Molecular Neurology, Charité-University Medicine and Max Delbruck Center for Molecular Medicine, Berlin, Germany.
Bendix
Ivo
I
Prozorovski
Timour
T
Ratner
Maya
M
Nazarenko
Irina
I
Pfueller
Caspar F
CF
Brandt
Alexander U
AU
Herz
Josephine
J
Brocke
Stefan
S
Ullrich
Oliver
O
Zipp
Frauke
F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D043803:Phenalenes / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D054876:Prenylation; D011485:Protein Binding; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D043803:Phenalenes; D011106:Polyisoprenyl Phosphates; C030462:atrovenetin; D006160:Guanosine Triphosphate; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D053148:Caspase 3; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate