[Metabolic pathways controlled by E3 ligases: an opportunity for therapeutic targeting]

Since its discovery, the Ubiquitin Proteasome System (UPS) has been recognized for its major role in controlling most of the cell's metabolic pathways. In addition to its essential role in the degradation of proteins, it is also involved in the addressing, signaling or repair of DNA, which makes it a key player in cellular homeostasis. Although other control systems exist in the cell, the UPS is often referred to as the conductor. In view of its importance, any dysregulation of the UPS leads to more or less severe disorders for the cell and therefore the body, which accounts for UPS implication in many pathologies (cancer, Alzheimer's disease, Huntington's disease, etc.). UPS is made up of more than 1000 different proteins, the combinations of which allow the fine targeting of virtually all proteins in the body. UPS uses an enzymatic cascade (E1, 2 members; E2 > 35; E3 > 800) which allows the transfer of ubiquitin, a small protein of 8.5 kDa onto the protein to be targeted either for its degradation or to modify its activity. This ubiquitinylation signal is reversible and many deubiquitinylases (DUB, ∼ 80 isoforms) also have an important role. E3 enzymes are the most numerous and their function is to recognize the target protein, which makes them important players in the specific action of UPS. The very nature of E3 and the complexity of their interactions with different partners offer a very broad field of investigation and therefore significant potential for the development of therapeutic approaches. Without being exhaustive, this review illustrates the different strategies that have already been implemented to fight against different pathologies (excluding bacterial or viral infections).