Zinc homeostasis and signaling in health and diseases

Toshiyuki Fukada 0 1 2 3 Satoru Yamasaki 0 1 2 3 Keigo Nishida 0 1 2 3 Masaaki Murakami 0 1 2 3 Toshio Hirano 0 1 2 3 0 K. Nishida Immune System, Cooperation Program, Graduate School of Frontier Biosciences, Osaka University , Osaka 565-0871, Japan 1 T. Fukada Laboratory of Allergy and Immunology, Graduate School of Medicine, Osaka University , Osaka 565-0871, Japan 2 T. Fukada S. Yamasaki K. Nishida T. Hirano Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology , Yokohama, Kanagawa 230-0045, Japan 3 M. Murakami T. Hirano (&) Laboratories of Developmental Immunology , JST-CREST, Graduate School of Frontier Biosciences, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University , Osaka 565-0871, Japan The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn's dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis. - The presence of zinc (Zn) was discovered in Aspergillus niger, the common bread mold, in the nineteenth century [1]. Zn was not recognized as indispensable for human life for almost another 100 years until the important discovery by Prasad et al. [2]. Although Zn salts and Zn-related compounds are normally colorless, unlike those of metals such as copper and iron, making a biological study of Zn more difficult, recent advances in life science research have contributed to unfolding its basic requirement for mammalian life [3], including the fact that Zn is pivotal for mammalian oocytogenesis, even before conception [4, 5]. The essential trace element Zn is a structural constituent in numerous proteins, including growth factors, cytokines, receptors, enzymes, and transcription factors belonging to cellular signaling pathways, and is essential for their biological activity [6, 7]. Emphasizing Zns physiological relevance to life, a human genome bioinformatics study revealed that approximately 10% of all proteins may bind with Zn [8]. The biological functions of these Zn-binding proteins would be maintained through cellular Zn levels, which are tightly controlled by Zn transporters and channels, and by Zn-sensing molecules such as metallothioneins (MTs) and metal-responsive-element-binding transcription factor-1 [914] (Fig. 1). Although many studies have focused on Zn homeostasis and its biological relevance, recent advances in cell biology and chemistry have highlighted the existence and activity of free or labile Zn in cellular responses, particularly its neurotransmitter activity in synaptic vesicles [15, 16]. Dynamic changes in Zn levels in the brain correlating to physiological experiences and long-term memories have been documented [17, 18], suggesting that free Zn is closely involved in neurotransmitter functions. There is increasing evidence that Zn not only acts as a neurotransmitter to mediate intercellular communication, but also acts as an intracellular signaling molecule, much like calcium (Ca) [19]. Our observation that nuclear retention of the Zn-finger transcription factor Snail requires the Zn transporter Zrt/Irt-like protein (ZIP) 6/Liv1, which in the zebrafish gastrula organizer depends on signal transducers and activators of transcription 3 (STAT3) activation (Fig. 2a) [20], led to a hypothesis that Zn acts as an intracellular signaling molecule. In this case, intracellular Zn levels might change in response to extracellular stimuli through changes in Zn transporter expression, affecting the Fig. 1 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-elementbinding transcription factor 1 (MTF1) within the cell, based on currently available information [30, 148154]. Arrows show the predicted direction of Zn mobilization. ER endoplasmic reticulum Fig. 2 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-b) 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 activation status of several intracellular signaling molecules, including Snail. There is growing evidence that Zn mediated by Zn transporters contributes to the regulation of intracellular signaling pathways (Fig. 2ae), as we will discuss shortly. We have proposed classifying intracellular Zn signals into transcription-independent early Zn signaling (EZS) and transcription-dependent late Zn signaling (LZS) [19] (Fig. 3). EZS occurs in the Zn wave phenomenon in mast cells, in which Zn levels change rapidly (within several minutes) upon extracellular stimulation [21]. In LZS, the intracellular Zn levels are altered several hours after extracellular stimulation, through changes in Zn transporter expression. Since many cytosolic proteins may have Zn-binding potential, both EZS and LZS are expected to be closely involved in a wide range of physiological responses, including development, immune functions, cancer progression, and hard and connective tissue disorders [19, 2224]. Here, we review new findings on the role of Zn signaling in physiological processes and disease status, and discuss the impact of EZS and LZS on biological events. 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-jB)-mediated cytokine production in mast cells under Fc epsilon receptor I (FceRI) 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 has wide-ranging effects on cellu (...truncated)