Post-translational modifications in disease
Proteins that contain the CAAX motif (C:cysteine, A: aliphatic residue, X:any amino acid) at their C terminus encompass a wide variety of molecules such as nuclear lamins, Ras as well as GTP-binding proteins (G proteins) Located at the cytoplasmic surface of cell membranes, they are involved in various signalling and regulatory processes. The CAAX motif directs protein post-translational modification, which occurs in three steps by four different enzymes (FTase, GGTase-I, RCE1, ICMT). Given the implication of some CAAX proteins in various diseases, inhibition of the enzymes that modify the CAAX motif has emerged as an attractive approach to interfere with CAAX protein localisation and function. The primary objective of the CAAXPROCESSINGHUMDIS (CAAX protein processing in human disease: from cancer to progeria) project was to understand the physiologic and medical importance of post-translational processing of CAAX proteins. From a clinical perspective, scientists wished to determine if enzymes processing the CAAX protein could serve as therapeutic targets for the treatment of cancer and progeria. Progeria is an aging-like condition associated with mutations in prelamin A. Project results challenged the current conception on CAAX processing with emphasis on the role of protein geranylgeranylation, the first step of the post-translational protein modification process. Until now, scientists thought that during geranylgeranylation, CAAX proteins become more hydrophobic, a pre-requisite for membrane binding and activation. The CAAXPROCESSINGHUMDIS project discovered that deletion of the enzyme responsible for geranylgeralylation led to an activation of CAAX proteins and to inflammatory conditions. Furthermore, reduction of the methyltransferase ICMT that carries out the last CAAX processing step eliminated progeria disease phenotype in mice. This exciting discovery led to the development of ICMT inhibitors for progeria treatment in children. Collectively, the results of the study challenged the current dogma regarding the role of a major protein post-translational modification process in CAAX activity. Importantly, it brought forward novel therapeutic targets for the treatment of cancer and progeria.
