RhoGDI: A rheostat for the Rho switch.

Regulation of the Rho switch has been typically centered on their main regulators, RhoGEFs and RhoGAPs. On the side, RhoGDI proteins have been considered mostly as passive regulators devoid of catalytic activity simply holding Rho proteins in the cytosol. In the May issue of Nature Cell Biology,1 we describe a novel evolutionary conserved function for RhoGDI1 as a chaperoning protein which prevents degradation of prenylated Rho GTPases. The limited amount of RhoGDI1 in cells generates a competitive balance between GTPases in order to prevent their degradation. Therefore, this creates a crosstalk regulatory mechanism of Rho proteins, whereby the level of one Rho protein can affect both the level and activity of the others. For example, overexpression of a single GTPase will promote the degradation and inactivation of all endogenous Rho proteins bound to GDI. These results suggest that some of the conclusions drawn from studies that manipulate Rho protein levels may need to be reevaluated. Here, we discuss some of the consequences of this mechanism on the regulation of Rho proteins, the dissociation of Rho-RhoGDI complexes by GDF and whether this regulation might be extended to other GTPases of the Ras superfamily.