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.