Roles of zinc and zinc signaling in immunity: Zinc as an intracellular signaling molecule

Zinc (Zn) is an essential nutrient required for cell growth, differentiation, and survival, and its deficiency causes growth retardation, immunodeficiency, and other health problems. Therefore, Zn homeostasis must be tightly controlled in individual cells. Zn is known to be important in the immune system, although its precise roles and mechanisms have not yet been resolved. Zn has been suggested to act as a kind of neurotransmitter. In addition, Zn has been shown to bind and affect the activity of several signaling molecules, such as protein tyrosine phosphatases (PTPs). However, it has not been known whether Zn itself might act as an intracellular signaling molecule, that is, a molecule whose intracellular status is altered in response to an extracellular stimulus, and that is capable of transducing the extracellular stimulus into an intracellular signaling event. Here we propose that Zn acts as a signaling molecule and that there are at least two kinds of Zn signaling: "late Zn signaling," which is dependent on a change in the expression profile of Zn transporters, and "early Zn signaling," which involves a "Zn wave" and is directly induced by an extracellular stimulus. We also review recent progress in uncovering the roles of Zn in the immune system.