The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective

Kimura, Toshikiro; Kambe, Taiho

doi:10.3390/ijms17030336

Cited by 353 publications

(304 citation statements)

References 165 publications

(195 reference statements)

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“…There are four different MT classes; MT-1 and MT-2 are ubiquitous though-out the body, their main function is to maintain cellular zinc homeostasis and chelate heavy metals to reduce cytotoxicity and lower their intracellular concentrations, and due to their radical oxygen species (ROS) scavenging properties they help protect against several types of environmental stress. MT-3 and MT-4 expression is restricted to a cell type-specific pattern, with MT-3 predominantly found in the brain and MT-4 is primarily located in stratified epithelial tissues [20,23].…”

Section: A Metallothioneins and Other Zinc Binding Proteinsmentioning

confidence: 99%

Zinc in Infection and Inflammation

Gammoh¹,

Rink²

2017

Preprint

187

139

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Abstract:Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors or differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B, a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli.

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Section: A Metallothioneins and Other Zinc Binding Proteinsmentioning

confidence: 99%

Zinc in Infection and Inflammation

Gammoh¹,

Rink²

2017

Preprint

187

139

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“…Covalently bound zinc is required for the activity of numerous enzymes and transcription factors (28). The zinc finger is an ancient structural motif capable of interacting with both DNA and RNA, and proteins containing this motif are the most-abundant class of proteins in the human proteome (29 transporters (30,(34)(35)(36). Synaptic Zn 2+ plays an essential role in modulating synaptic transmission throughout the brain (37-40), including the retina, where it contributes to neuromodulation and neuroprotection (41, 42).…”

mentioning

confidence: 99%

“…The zinc finger is an ancient structural motif capable of interacting with both DNA and RNA, and proteins containing this motif are the most-abundant class of proteins in the human proteome (29). Mobile or chelatable zinc (Zn 2+ ) is concentrated in synaptic vesicles and other intracellular organelles (30) transporters (30,(34)(35)(36). Synaptic Zn 2+ plays an essential role in modulating synaptic transmission throughout the brain (37)(38)(39)(40), including the retina, where it contributes to neuromodulation and neuroprotection (41,42).…”

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confidence: 99%

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Andereggen

Yuki

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

129

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Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn 2+ ) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn 2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn 2+ accumulation in amacrine cell processes involves the Zn 2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn 2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn 2+ chelation extends for several days after nerve injury. These results show that retinal Zn 2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn 2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.T he optic nerve has been widely used to investigate the response of CNS neurons to injury because of its accessibility, anatomy, and functional importance. Under normal circumstances, retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate axons after the optic nerve has been damaged and soon undergo cell death, leaving victims of traumatic or ischemic nerve injury or degenerative conditions, such as glaucoma, with permanent visual losses. Optic nerve injury leads to numerous pathological changes in RGCs and reversing some of these changes improves cell survival, although these effects are often transitory and for the most part promote little or no axon regeneration (1-10). Regeneration per se can be induced by intraocular inflammation combined with elevated cAMP (11, 12), counteracting cell-intrinsic (13-15) or cellextrinsic (16, 17) suppressors of axon growth, oncomodulin and other growth factors (18-22), or elevated physiological activity (23,24). Some of these treatments act synergistically and enable a modest number of RGCs to reestablish connections with appropriate target areas in the brain (25-27). However, although these studies show that successful regeneration can occur in principle, most RGCs eventually die after optic nerve injury, and to date only a small fraction of surviving RGCs have been induced to regenerate axons (27). These observations imply the existence of other major, as yet unknown suppressors of cell survival and regeneration. Our results point to zinc dysregulation as a critical factor.Zinc is essential for many cellular functions. Covalently bound zinc is required for the activity of numerous enzymes and t...

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“…Formation of thionin results from oxidation of zinc-bound metallothionein, linking the redox state of the cells to zinc homeostasis (17). Metallothioneins act in concert with zinc transporters from the SLC39 family (ZIP) involved in zinc uptake and from the SLC30 (ZnT) family responsible for zinc transport into organelles or out of cells (6,18). Free zinc ions are thought to serve as signaling ions (19); several studies indicate that free zinc activates different pathways and can modulate the insulin and mTOR pathways (20,21).…”

mentioning

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Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

Summermatter

Bouzan

Pierrel

et al. 2017

Molecular and Cellular Biology

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Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.KEYWORDS muscle metabolism S keletal muscle hypertrophy is characterized in the adult mammal by an increase in the size of preexisting myofibers. The induction of hypertrophy involves an activation of the pathways that increase protein synthesis and inhibition of cellular signaling, which induces protein degradation. Hypertrophy can be induced by the activation of Akt, through multiple potential inputs (1). Akt induces hypertrophy in part by activating the mTOR/70S6 kinase pathway. In addition, Akt inhibits protein degradation, by phosphorylating and therefore blocking Foxo1 and Foxo3-transcription factors which are required for the upregulation of the E3 ubiquitin ligases MuRF1 and MAFbx, which help mediate protein turnover during muscle atrophy (2-4). Therefore, activation of Akt constitutes a critical signaling node to increase muscle hypertrophy and block muscle atrophy (1).Mammalian metallothioneins (MTs) belong to a family of cysteine-rich, metalbinding proteins. In rodents, four MT isoforms have been identified: the two major isoforms, MT-1 and MT-2, are ubiquitously expressed, while MT-3 and MT-4 show tissue specific expression in the central nervous system and squamous epithelia, respectively. In humans, multiple isoforms have been reported for MT-1 (MT-1A, MT-1B, MT-1E, MT-1F, MT-1G, MT-1H, MT-1M, and MT-1X), while no splice variants are documented for MT-2, MT-3, or MT-4 (5; for a review, see reference 6).MTs play a role in cellular zinc homeostasis, mitochondrial function (7), defense against oxidative stress (8), and defense against inflammation (5). Moreover, several reports and a recent review highlight a role of metallothioneins in cancer (9), aging (10), and the onset of particular central nervous system diseases (11).

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The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective

Cited by 353 publications

References 165 publications

Zinc in Infection and Inflammation

Zinc in Infection and Inflammation

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

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