Protein isoprenylation in biology and disease: general overview and perspectives from studies with genetically engineered animals

The posttranslational modification of proteins by lipids is a key mechanism in the regulation of protein localization and function. Isoprenylation is a process critical for the membrane association of a plethora of signalling proteins with fundamental roles in cell biology, including G proteins and nuclear lamins. Isoprenylation is irreversible but is frequently associated to reversible posttranslational modifications, such as palmitoylation or phosphorylation, that act like switches that modulate the dynamics of protein-membrane or protein-protein interactions and target the modified proteins to specific membrane compartments. The severe phenotype of animals deficient in the enzymes involved in isoprenylation and postprenylation processing highlights the significance of these processes. Moreover, alterations in the genes involved in the maturation of isoprenylated proteins have been found at the basis of some severe human diseases, like choroideremia or the premature ageing progeria syndromes. Given their critical role in the transformation potential of the Ras oncogenes, isoprenylation and postprenylation processing are targets for the development of inhibitors with antitumoral activity. The recent generation of animal models genetically engineered to target the enzymes involved in isoprenylation and associated modifications has unveiled unpredicted aspects of these modifications. Moreover, these models are proving of crucial importance for the elucidation of the mechanisms of disease, and the identification and validation of therapeutic targets. This review attempts to summarize general aspects of the posttranslational modification of proteins by isoprenylation, paying special attention to the evidences obtained from the use of genetically engineered animals and the avenues that these models open.