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 post translational modification may be manipulated by agents such as3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMGCRIs) that prevent de novo synthes is of isoprenoids such as GGpp. HMGCRI shave anti-inflammatory properties and substantially reduce infiltration of inflammatory immune cells into target tissues, including the central nervous system (CNS) during neuro inflammation. The depletion of the cellular is oprenoid pool is believed to result in the regulation of antigen specific T cells outside the target organand also to prevent migration of these cells in to target organs, such as the CNS. In vivo treatment with HMGCRI in the experimental autoimmune encephalitis (EAE) rodent model of multiple scleros is reduces the capacity of activated T cells to traffic to and with in the brain. This presentation shows that geranylgeranylation is fundamental for Rho Am ediated down stream events such as influencingcy to skeletal organization and the migration of T cells. Tethering of RhoA to them embrane by GGppis necessary for T cell migration and provides a mechanism by which HMGCRI may prevent T cell infiltration into inflamed compartments.