Subcellular localization of zinc (Zn) transporters and metallothioneins (MTs). Localization and potential functions of Zn transporters from the Slc39/Zrt/Irt-like protein (ZIP) (blue) and Slc30/ZnT (red) families, MT, and metal-responsive-element-binding transcription factor 1 (MTF1) within the cell, based on currently available information [30, 148–154]. Arrows show the predicted direction of Zn mobilization. ER endoplasmic reticulum

Early and late Zn signaling. Intracellular Zn signaling falls into two types: early Zn signaling (left), in which an extracellular stimulus directly induces elevated Zn levels within several minutes by releasing Zn from a Zn store such as ER or MTs, and late Zn signaling (right), which is induced several hours after stimulation and is dependent on a transcriptional change in Zn transporter expression. Zn waves in mast cells are an example of early Zn signaling (see Fig. 6)

Zn suppresses T helper 17 (Th17) cell development by inhibiting STAT3 activation. Peripheral naive CD4⁺ T cell precursor cells can differentiate into three subsets of effector T cells (Th1, Th2, and Th17). The differentiation of these subsets is governed by selective cytokines, and each subset accomplishes specialized functions. Th17 cells, which are critical for the development of inflammation and autoimmune disease, are induced by IL-6 and tumor necrosis factor beta (TGF-β). Zn directly binds STAT3, inhibiting its activation by IL-6 and suppressing autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). P tyrosine phosphorylation

Model for Zn release for the generation of Zn signaling. a Labile Zn in intracellular Zn storage moves through “Zn gatekeepers” into the cytosol, and approaches target molecules. The Zn gatekeepers are closed in the steady state, but are opened by changes in activation status. b Most of the Zn in the cytosol is sequestered in MTs, and is detached from the MTs by intracellular oxidative stress. The rapid increase in intracellular Zn mediated by cellular events may act as an early Zn signaling to change the status of target molecules

Roles of ZIP and ZnT Zn transporter family members in intracellular signaling. a The signal transducers and activators of transcription 3 (STAT3) downstream target ZIP6 is required for nuclear translocation of the Zn-finger transcription factor Snail, which regulates gastrular cell movement in zebrafish. b ZIP13 is required for the nuclear translocation of Smads in bone morphogenetic protein (BMP)/transforming growth factor beta (TGF-β) signaling, and is involved in tooth, bone, and connective tissue development. c ZIP14, which facilitates G protein-coupled receptor (GPCR) signaling by inhibiting hormone-stimulated phosphodiesterase (PDE) in the pituitary gland, liver, and cartilage, is required for endocrine reactions and systemic growth. d ZnT5 controls protein kinase C (PKC) translocation to the plasma membrane, leading to nuclear factor kappa B (NF-κB)-mediated cytokine production in mast cells under Fc epsilon receptor I (FcεRI) signaling. e Lipopolysaccharide (LPS) stimulation alters the expression of ZIP and ZnT family Zn transporters, resulting in downregulated intracellular Zn levels, followed by dendritic cell maturation and immune responses. TLR Toll-like receptor

Zn and Zn transporters are indispensable for FcεRI-mediated mast cell activation. Zn is required for multiple steps of FcεRI-induced mast cell activation, including degranulation and cytokine production. Cytosolic Zn regulates the FcεRI-induced granule translocation process, which is mediated by a Fyn/Grb2-associated binder 2 (Gab2)/Ras homologue gene family member A (RhoA)-mediated calcium-independent pathway. Zn and ZnT5 are also required for the translocation of PKC to the plasma membrane and the subsequent nuclear translocation of NF-κB, which leads to the production of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). IKKβ I-kappa B kinase beta, IkBα I-kappa B alpha

FcεRI increases intracellular free Zn levels, Zn wave: a type of early Zn signaling. a The intracellular Zn level increases within several minutes after antigen stimulation. To monitor the intracellular Zn level, mast cells were treated with the cell-permeable fluorescent Zn indicator Newport Green. Newport Green fluorescence remained steady in the cytoplasm, but gradually increased in the perinuclear and nuclear areas upon FcεRI stimulation. We named this phenomenon a “Zn wave.” b Early Zn signaling in mast cells. Extracellular antigen stimulation induces a Zn wave—a rapid alteration in intracellular Zn level—through the activation of Ca²⁺ and extracellular-signal-regulated kinase 1 and 2 (Erk1/2) signaling, which might positively affect the signal for inflammatory cytokine-mediated allergic reactions. This suggests that Zn has a role as an intracellular signaling molecule, transducing extracellular stimuli to physiological responses. Violet ovals Zn gatekeepers. (a Modified from Yamasaki et al. [21])