Protein trafficking abnormalities in<i>Drosophila</i>tissues with impaired activity of the ZIP7 zinc transporter Catsup

Groth, Casper; Sasamura, Takeshi; Khanna, Mansi R.; Whitley, Michael; Fortini, Mark E.

doi:10.1242/dev.088336

Cited by 74 publications

(73 citation statements)

References 51 publications

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“…However, the key role of Zn in cellular functions combined with defects in Zn management noted in ZnT2-null mice and cells expressing ZnT2 variants implicates genetic variation in ZnT2 in breast cell dysfunction. Specifically, variants retained in the ER (e.g., K 66 N, A 28 D, Q 71 H, A 105 P, D 103 E and T 288 S) or that affect mitochondrial Zn transport (e.g., Q 71 H, and A 105 P) could activate ER stress or cell death pathways [45,46], lower the apoptotic threshold or affect ATP production [6]. Additionally, preservation of normal cell cycle/DNA damage check-point controls is important during pubertal growth and development, during ductal/ alveolar morphogenesis and expansion during pregnancy and lactation, as well as for the massive degree of programed cell death that occurs during involution upon weaning.…”

Section: Genetic Variation In Slc30a2 Affects Breast Epithelial Cell mentioning

confidence: 99%

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

Alam

Hennigar

Gallagher

et al. 2015

J Mammary Gland Biol Neoplasia

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The zinc (Zn) transporter ZnT2 (SLC30A2) is expressed in specialized secretory cells including breast, pancreas and prostate, and imports Zn into mitochondria and vesicles. Mutations in SLC30A2 substantially reduce milk Zn concentration ([Zn]) and cause severe Zn deficiency in exclusively breastfed infants. Recent studies show that ZnT2-null mice have low milk [Zn], in addition to profound defects in mammary gland function during lactation. Here, we used breast milk [Zn] to identify novel non-synonymous ZnT2 variants in a population of lactating women. We also asked whether specific variants induce disturbances in intracellular Zn management or cause cellular dysfunction in mammary epithelial cells. Healthy, breastfeeding women were stratified into quartiles by milk [Zn] and exonic sequencing of SLC30A2 was performed. We found that 36% of women tested carried non-synonymous ZnT2 variants, all of whom had milk Zn levels that were distinctly above or below those in women without variants. We identified 12 novel heterozygous variants. Two variants (D(103)E and T(288)S) were identified with high frequency (9 and 16%, respectively) and expression of T(288)S was associated with a known hallmark of breast dysfunction (elevated milk sodium/potassium ratio). Select variants (A(28)D, K(66)N, Q(71)H, D(103)E, A(105)P, Q(137)H, T(288)S and T(312)K) were characterized in vitro. Compared with wild-type ZnT2, these variants were inappropriately localized, and most resulted in either 'loss-of-function' or 'gain-of-function', and altered sub-cellular Zn pools, Zn secretion, and cell cycle check-points. Our study indicates that SLC30A2 variants are common in this population, dysregulate Zn management and can lead to breast cell dysfunction. This suggests that genetic variation in ZnT2 could be an important modifier of infant growth/development and reproductive health/disease. Importantly, milk [Zn] level may serve as a bio-reporter of breast function during lactation.

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Section: Genetic Variation In Slc30a2 Affects Breast Epithelial Cell mentioning

confidence: 99%

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

Alam

Hennigar

Gallagher

et al. 2015

J Mammary Gland Biol Neoplasia

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“…A Catsup mutant, in which dZip7 is defective, shows abnormally high levels of catecholamines and is probably semi-dominant lethal (386). The mutant also exhibits defects in membrane protein trafficking and elevated ER stress (129). In contrast to mammalian ZIP13, dZip13 is identified as an iron exporter to supply iron into the secretory pathway (450).…”

Section: Role Of Zinc Transporters In Zinc Homeostasis and Metabolismmentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

873

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…-signaling pathways by phosphorylating ZIP7 (18) while some studies have also highlighted its important contribution to Zn 2+ -homeostasis, particularly under pathological conditions (19)(20)(21).…”

Section: +mentioning

confidence: 99%

Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

et al. 2017

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Changes in cellular free Zn 2+ concentration, including those in the sarco(endo)plasmic reticulum [S(E)R], are primarily coordinated by Zn 2+-transporters whose identity and role in the heart is not well established. Here, we hypothesized that ZIP7 and ZnT7 transport Zn 2+ in opposing directions across the S(E)R membrane in cardiomyocytes and that changes in their activity may play an important role in the development of ER-stress during hyperglycemia.The subcellular S(E)R-localization of ZIP7 and ZnT7 was determined in cardiomyocytes and in isolated S(E)R-preparations. Markedly increased mRNA and protein levels of ZIP7 were observed in ventricular cardiomyocytes from diabetic rats or high glucose-treated H9c2 cells whilst ZnT7 expression was low. Additionally, we observed increased ZIP7-phosphorylation in response to high glucose in vivo and in vitro. Using recombinant targeted FRET-based sensors, we showed that hyperglycemia induced a marked redistribution of cellular free Zn 2+ , increasing cytosolic free Zn 2+ and lowering free Zn 2+ in the S(E)R. These changes involve alterations in ZIP7-phosphorylation and were suppressed by siRNA-mediated silencing of CK2α. Opposing changes in the expression of ZIP7 and ZnT7 were also observed in hyperglycemia. We conclude that sub-cellular free Zn 2+ re-distribution in the hyperglycemic heart, resulting from altered ZIP7 and ZnT7 activity, contributes to cardiac dysfunction in diabetes.

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Protein trafficking abnormalities inDrosophilatissues with impaired activity of the ZIP7 zinc transporter Catsup

Cited by 74 publications

References 51 publications

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Hyperglycemia-Induced Changes in ZIP7 and ZnT7 Expression Cause Zn2+ Release From the Sarco(endo)plasmic Reticulum and Mediate ER Stress in the Heart

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