Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate.

Zinc is an essential trace element for life. Zinc is not only an important nutrient, cofactor of numerous enzymes and transcription factors, but also it acts as an intracellular mediator, similarly to calcium. The recent discovery of its intracellular molecular pathways opens the door to new fields of drug design. Zinc homeostasis results from a coordinated regulation by different proteins involved in uptake excretion and intracellular storage/trafficking of zinc. These proteins are membranous transporters, belonging to the ZIP and ZnT families, and metallothioneins. Their principal function is to provide zinc to new synthesized proteins, important for several functions such as gene expression, immunity, reproduction or protection against free radicals damage. Zinc intracellular concentration is correlated to cell fate, ie proliferation, differentiation or apoptosis, and modifications of zinc homeostasis are observed in several pathologies affecting humans at any stage of life. Two zinc-related diseases, acrodermatitis enteropathica and the lethal milk syndrome, have been recently related to mutations in zinc transporters, SLC39A4 and ZnT-4, respectively. Zinc acts as an inhibitor of apoptosis, while its depletion induces programmed cell death in many cell lines. However, excess zinc can also be cytotoxic, and zinc transporters as well as metallothioneins serve as zinc detoxificating systems. Several zinc channels, controlling the intracellular zinc movements and the free form of the metal, maintain the intracellular zinc homeostasis, and thus the balance between life and cell death. Apart from these general activities, zinc has particular biological roles in some specialized cells. It acts as a paracrine regulator in pancreatic cell, neuron or neutrophil activity by a mechanism of vesicles-mediated metal excretion and uptake. A well knowledge on zinc transporters will be useful to develop new molecular targets to act on these zinc-regulated biological functions.