Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway - PubMed (original) (raw)

Review

Understanding the Contribution of Zinc Transporters in the Function of the Early Secretory Pathway

Taiho Kambe et al. Int J Mol Sci. 2017.

Abstract

More than one-third of newly synthesized proteins are targeted to the early secretory pathway, which is comprised of the endoplasmic reticulum (ER), Golgi apparatus, and other intermediate compartments. The early secretory pathway plays a key role in controlling the folding, assembly, maturation, modification, trafficking, and degradation of such proteins. A considerable proportion of the secretome requires zinc as an essential factor for its structural and catalytic functions, and recent findings reveal that zinc plays a pivotal role in the function of the early secretory pathway. Hence, a disruption of zinc homeostasis and metabolism involving the early secretory pathway will lead to pathway dysregulation, resulting in various defects, including an exacerbation of homeostatic ER stress. The accumulated evidence indicates that specific members of the family of Zn transporters (ZNTs) and Zrt- and Irt-like proteins (ZIPs), which operate in the early secretory pathway, play indispensable roles in maintaining zinc homeostasis by regulating the influx and efflux of zinc. In this review, the biological functions of these transporters are discussed, focusing on recent aspects of their roles. In particular, we discuss in depth how specific ZNT transporters are employed in the activation of zinc-requiring ectoenzymes. The means by which early secretory pathway functions are controlled by zinc, mediated by specific ZNT and ZIP transporters, are also subjects of this review.

Keywords: ER stress; ZIP/SLC39A; ZNT/Solute carrier family 30 member (SLC30A); early secretory pathway; metallation; tissue non-specific alkaline phosphatase (TNAP); unfolded protein response (UPR); zinc-requiring ectoenzymes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Subcellular localization of ZNT and ZIP transporters. ZNT transporters move cytosolic zinc into the lumen of vesicles involved in the early secretory pathway, including the endoplasmic reticulum (ER), Golgi apparatus, as well as into cytoplasmic vesicles/granules such as synaptic and secretory vesicles and insulin granules, in which specific ZNT proteins are localized. ZNT5 and ZNT6 form heterodimers to transport zinc. ZIP transporters move zinc in the opposite direction. In contrast to the specific localization of ZIP9, ZIP13, and ZIP7 in the Golgi apparatus and the ER, the subcellular location of ZNT5-ZNT6 heterodimers has not been definitively determined.

Figure 2

Figure 2

Phylogeny of ZNT and ZIP transporters. The neighbor-joining phylogenetic tree was constructed using ClustalW (

http://clustalw.ddbj.nig.ac.jp/index.php?lang=en

) protein alignment. (A) ZNT and (B) ZIP transporters. Subfamilies and subgroups are designated according to the text.

Figure 3

Figure 3

Model of feedback regulation for the maintenance of zinc homeostasis in the ER (in the early secretory pathway). A disturbance in zinc homeostasis, such as zinc deficiency or zinc overload, in the ER (and perhaps in the early secretory pathway) induces homeostatic ER stress. The unfolded protein response (UPR) leads to the activation of transcription factors such as ATF4, ATF6, and XBP1, and increases the transcription of several ZNT and ZIP transporter genes. These activities of ZNT and ZIP transporters then contribute to the maintenance of zinc homeostasis in the ER (and in the early secretory pathway), and thus attenuate homeostatic ER stress. Zn: zinc.

Figure 4

Figure 4

ZNT5-ZNT6 heterodimers and ZNT7 homodimers function to activate tissue-nonspecific ALP (TNAP) in a two-step mechanism. TNAP is specifically activated in a two-step mechanism involving ZNT5-ZNT6 heterodimers and ZNT7 homodimers as follows: first, the apo-form of TNAP is stabilized by either ZNT5-ZNT6 heterodimers or ZNT7 homodimers; second, the apo-form of TNAP is converted to the _holo_-form by zinc metallation. The PP-motifs in ZNT5 and ZNT7 likely play important roles in this process (see text). TNAP possesses a bimetallic core, is dimeric, and is localized to the plasma membrane via a glycophosphatidylinositol anchor. The subcellular localizations of ZNT5-ZNT6 heterodimers or ZNT7 homodimers have not been well defined. Zn: zinc.

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