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(ZIP7) Is Essential for Regulation of Cytosolic Zinc Levels S Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2018/07/06/mol.118.112557.DC1 1521-0111/94/3/1092–1100$35.00 https://doi.org/10.1124/mol.118.112557 MOLECULAR PHARMACOLOGY Mol Pharmacol 94:1092–1100, September 2018 Copyright ª 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. The Zinc Transporter SLC39A7 (ZIP7) Is Essential for Regulation of Cytosolic Zinc Levels s Grace Woodruff, Christian G. Bouwkamp, Femke M. de Vrij, Timothy Lovenberg, Pascal Bonaventure, Steven A. Kushner, and Anthony W. Harrington Neuroscience Discovery, Janssen Research and Development, San Diego, California (G.W., T.L., P.B., A.W.H.); and Department of Psychiatry, Erasmus MC, Rotterdam, The Netherlands (C.G.B., F.M.V., S.A.K.) Received March 22, 2018; accepted June 28, 2018 Downloaded from ABSTRACT Zinc homeostasis is a highly regulated process in mammalian increased ER zinc levels, impaired cell proliferation, and in- cells that is critical for normal growth and development. duction of ER stress. Confirmatory of impaired zinc transport as Movement of zinc across cell compartments is controlled by the causal mechanism, both the increased ER stress and two classes of transporters: Slc39a family members transport impaired cell proliferation were rescued by increasing cytosolic zinc into the cytosol from either the extracellular space or zinc. Furthermore, using these robust cellular phenotypes, we molpharm.aspetjournals.org intracellular stores such as the endoplasmic reticulum (ER), implemented a small-molecule library screen with 2800 com- whereas the SLC30A family mediates zinc efflux from the pounds and identified one small molecule capable of rescuing cytosol. In this study, we report that genetic ablation of ER stress and cell proliferation in ZIP7-deficient cells in the low SLC39A7 (ZIP7) results in decreased cytosolic zinc levels, micromolar range. Introduction childhood-onset parkinsonism-dystonia (Tuschl et al., 2016); and mutations in SLC39A13 (ZIP13) cause a form of Ehlers– Zinc is an essential metal that is required for normal growth Danlos syndrome (Giunta et al., 2008). Additionally, single- at ASPET Journals on September 28, 2021 and development in all higher plants and animals. Acting as a nucleotide polymorphisms and copy number variations in cofactor for over 2000 proteins, zinc can modulate enzymatic other ZnT and ZIP family members have been associated with activity and gene transcription (Hogstrand et al., 2009), as bipolar disorder (Baum et al., 2008), schizophrenia (Carrera well as function as a second messenger in signaling pathways et al., 2012), autism (O’Roak et al., 2011; Gazzellone et al., (Yamasaki et al., 2007). Because zinc cannot freely permeate 2014), and other disorders (Kambe et al., 2015). Thus, lipid bilayers, active transport is required to move zinc across elucidating the function of individual zinc transporters may cellular and organelle membranes. There are two families of help us understand the pathophysiology, treatment, and zinc transporters, categorized by their direction of zinc prevention of zinc-related disease conditions. movement. The solute carrier family 30A (SLC30A), also ZIP7 is the only known ZIP family member that is localized known as the Zn transporter (ZnT) family, has 10 members to the ER membrane and is hypothesized to be responsible for that mobilize zinc from the cytosol. The solute carrier family mobilizing zinc from the ER, a zinc storage site, into the 39A (SLC39A) family, also known as the Zrt-, Irt-related cytosol (Taylor et al., 2004). ZIP7 is critical for normal growth protein (ZIP) family, has 14 members that transport zinc into and development as the ZIP7 knockout (KO) is embryonic the cytosol from the extracellular space or from intracellular lethal in mice, whereas loss-of-function mutations of the stores, such as the ER and Golgi. In addition to zinc, some drosophila ZIP7 homolog Catecholamines up (Catsup) lead members of the ZIP family also transport iron (Pinilla-Tenas to abnormal wing development (Groth et al., 2013). Furthermore, et al., 2011), manganese (Girijashanker et al., 2008), and morpholino knockdown of ZIP7 expression in zebrafish causes cadmium (Fujishiro et al., 2012). neurodevelopmental impairments, which can be rescued with Recent publications have identified the importance of ZnT zinc supplementation (Yan et al., 2012). At the cellular level, and ZIP transporters in human health and disease. Mutations recent studies have illuminated a role for ZIP7 in the normal in SLC39A8 cause intellectual disability with cortical atrophy function of the ER and shown that loss of ZIP7 results in ER (Boycott et al., 2015); mutations in SLC39A14 (ZIP14) cause stress (Ohashi et al., 2016; Bin et al., 2017). However, the precise mechanism of how loss of ZIP7 causes ER stress and affects zinc https://doi.org/10.1124/mol.118.112557. s This article has supplemental material available at molpharm. levels has not been fully elucidated. In this work, we report aspetjournals.org. that clustered regularly interspaced short palindromic repeats ABBREVIATIONS: CHOP, CCAAT enhancer-binding protein homologous protein; CRISPR, clustered regularly interspaced short palindromic repeats; ER, endoplasmic reticulum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GO, Gene Ontology; ICP-MS, inductively coupled plasma mass spectrometry; KO, knockout; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDI, protein disulfide isomerase; RNA-seq, RNA sequencing; WT, wild-type; ZIP, Zrt-, Irt-related protein; ZnT, Zn transporter. 1092 ZIP7 Maintains Cytosolic Zinc Levels 1093 (CRISPR)-mediated genetic ablation of ZIP7 in human cells follows: goat anti-rabbit Alexa Flour 488, goat anti-mouse Alexa Flour results in severely decreased levels of cytosolic zinc, impaired cell 488, and goat anti-rabbit Alexa Flour 568 all from ThermoFisher were proliferation, and activation of ER stress. Moreover, we demon- used at 1:500. In every experiment, five images per well were captured  strate the causality of the impaired cytosolic zinc levels by fully at 20 magnification, and each experiment was performed in triplicate rescuing both the impairment of cell proliferation and activation and repeated a minimum of three times. Images were analyzed using Harmony Image Analysis System (PerkinElmer). Please see the of ER stress by restoring cytosolic zinc levels. Finally, we Supplemental Data for more detail on image analysis. GraphPad Prism implemented a small-molecule screen based on the ER stress version 7 was used to perform all statistical analysis. All statistical tests phenotype that yielded a lead compound with efficacy in fully were unpaired. rescuing the effects of ZIP7 KO through a zinc-independent Phenotypic Screen. ZIP72/2 cells were plated at a density mechanism. of 1500 cells/well into 384-well Cell Carrier Ultra microplates (PerkinElmer). Twenty-four hours after plating, cells were treated with 1 mM compound. Pyrithione was used as the positive control at 500 nM. Cells were fixed with 4% paraformaldehyde 48 hours after Materials and Methods compound treatment. In the primary screen, cells were stained with Cell Culture and Genome Editing. MG-63 cells were grown CHOP and HCS CellMask Deep Red Stain, as described above, and in Eagle’s minimum essential media supplemented with 10% fetal the CHOP nucleus/cytoplasm ratio was calculated using Columbus bovine serum, 1 Pen/Strep, 1 non-essential amino acids, and 1 Image Analysis system. Hits were selected based on percentage of Downloaded from glutamine. Cells were split with trypsin every 3 to 4 days. MG-63 cells inhibition of CHOP. Pyrithione was set as 100% inhibition, and hits were transfected with Lipofectamine 3000 (Thermofisher, Carlsbad, were determined based on 70% inhibition or above. In the secondary CA) and SpCas9 plasmid with single guide RNA sequence: GCCA- screen, the 33 hits from the primary screen were retested at 1 mMin CACTCACGAGAGCATCTGG. This single guide RNA sequence tar- triplicate for 48 hours. In the secondary screen, cells were stained with gets exon 1 of SLC39A7. Seventy-two hours after transfection, green CHOP, HCS Cell Mask, and PDI, as described above. Of the 33 primary fluorescent protein (GFP)–positive cells were sorted and plated at a hits, 30 of them confirmed to inhibit CHOP in the secondary screen. density of 5000 cells per 10-cm dish, such that single colonies could be One compound (compound A) was identified to not only inhibit CHOP, molpharm.aspetjournals.org isolated. Clones were manually picked when colonies were ∼100 cells. but also increased cell number and reduced PDI intensity and area. Colonies were expanded and screened for ZIP7 KO based on Synthesis of Compound A. The synthesis of compound A is disruption of DNA sequence and confirmed as KO by Western blot. described in U.S. Patent US2008/080081 in example 24 (Illig et al., Cell lines were routinely checked to be free of mycoplasma infection 2016). using Lonza MycoAlert Mycoplasma Detection Kit (LT07; Lonza, Zinc Quantification by Inductively Coupled Plasma Mass Basel, Switzerland). Spectrometry. Cells were plated in 10-cm dishes and were Western Blot. Cells were lysed using radioimmunoprecipitation harvested 72 hours after plating. Dishes were treated with either assay buffer (ThermoFisher) with protease (Sigma-Aldrich, St. Louis, vehicle (H2O) or 500 nM pyrithione. Equal number of cells was MO) and phosphatase (Pierce, Waltham, MA) inhibitors. After fractionated to cytosol and ER fractions by first collecting cells and centrifugation at 13,000g, protein concentration was measured using spinning down at 300g. Supernatant was removed, and cells were at ASPET Journals on September 28, 2021 the bicinchoninic acid protein assay kit (Pierce) and lysates were resuspended in sucrose buffer (0.32 M sucrose 1 10 mM HEPES). separated on 4%–12% Bis–Tris gels (Invitrogen, Carlsbad, CA) using Cells were homogenized by syringe-based homogenization. Next, 4-morpholineethanesulfonic acid sodium dodecyl sulfate running buffer homogenized cells were spun at 300g for 10 minutes to remove nuclei.
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