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.
Highlights
Zinc is an essential trace element that is required for a large variety of cellular processes [1,2]
Zinc plays a pivotal role in the function of a variety of subcellular compartments, one of which is the early secretory pathway constituted by the endoplasmic reticulum (ER), the Golgi apparatus, and other intermediate organelles, such as the ER-Golgi intermediate compartment
Based on the crucial functions of zinc mobilized by Zn transporters (ZNTs) and Zrt- and Irt-like proteins (ZIPs) transporters in the early secretory pathway, it is easy to imagine that the transcription of ZNT and ZIP genes would be regulated by homeostatic ER stress
Summary
Zinc is an essential trace element that is required for a large variety of cellular processes [1,2]. ZNT7 is located in the Golgi apparatus [58], and a recent study indicates that it is localized to the sarco(endo)plasmic reticulum (S(E)R) [52] (Figure 1) These ZNT transporters are employed as zinc entry routes in the early secretory pathway, suggesting that a lack of them would be potentially to elicit an ER stress response. Of the 14 ZIP transporters, ZIP7, ZIP9, and ZIP13 (the ZIPI subfamily and the LIV-1 subgroup (iii) described above) are involved in the early secretory pathway [64,65,66,67] (Figure 1), recent reports indicate that ZIP9 is found localized on the plasma membrane where it serves as a membrane androgen receptor [68] and 5 of 18 5 of 18. The molecular basis underlying this phenomenon may be explained by changes in the activity of chaperone proteins that are either positively or negatively regulated by zinc [46,47,48], this has not yet been completely elucidated
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