Geranylgeranylation but not GTP-loading of Rho GTPases determines T cell function.
Rho guanosine triphosphatases (GTPases) orchestrate signaling pathways leading to cell migration. They are typically responsible for the organization of actin filaments that support actomyosin contractility and cell-body translocation. The function of Rho GTPases depends on GTP-loading and isoprenylation by geranylgeranyl pyrophosphate (GGpp). The latter posttranslational modification may be manipulated by agents such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMGCRIs) that prevent de novo synthesis of isoprenoids such as GGpp. HMGCRIs have anti-inflammatory properties and substantially reduce infiltration of inflammatory immune cells into target tissues, including the central nervous system (CNS) during neuroinflammation. The depletion of the cellular isoprenoid pool is believed to result in the regulation of antigen-specific T cells outside the target organ and also to prevent migration of these cells into target organs, such as the CNS. In vivo treatment with HMGCRI in the experimental autoimmune encephalitis (EAE) rodent model of multiple sclerosis reduces the capacity of activated T cells to traffic to and within the brain. This presentation shows that geranylgeranylation is fundamental for RhoA-mediated downstream events such as influencing cytoskeletal organization and the migration of T cells. Tethering of RhoA to the membrane by GGpp is necessary for T cell migration and provides a mechanism by which HMGCRI may prevent T cell infiltration into inflamed compartments.
Waiczies
Sonia
S
Cecilie Vogt Clinic for Molecular Neurology, Charité-University Medicine Berlin and Max Delbruck Center for Molecular Medicine, 10117 Berlin, Germany. sonia.waiczies@charite.de
Bendix
Ivo
I
Zipp
Frauke
F
D000818:Animals; D001921:Brain / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D003599:Cytoskeleton / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006160:Guanosine Triphosphate / Q000276:immunology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000276:immunology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology; D011106:Polyisoprenyl Phosphates / Q000276:immunology; D017368:Protein Prenylation / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D020741:rho GTP-Binding Proteins / Q000276:immunology*; D020742:rhoA GTP-Binding Protein
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D006160:Guanosine Triphosphate; D006903:Hydroxymethylglutaryl CoA Reductases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate