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The Human ABCB6 Protein Is the Functional Homologue of HMT-1 Proteins Mediating Cadmium… a 1

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The Human ABCB6 Protein Is the Functional Homologue of HMT-1 Proteins Mediating Cadmium… a 1 Cellular and Molecular Life Sciences https://doi.org/10.1007/s00018-019-03105-5 Cellular andMolecular Life Sciences ORIGINAL ARTICLE The human ABCB6 protein is the functional homologue of HMT‑1 proteins mediating cadmium detoxifcation Zsófa Rakvács1 · Nóra Kucsma1 · Melinda Gera1 · Barbara Igriczi1 · Katalin Kiss1 · János Barna2 · Dániel Kovács2 · Tibor Vellai2 · László Bencs4 · Johannes M. Reisecker5 · Norbert Szoboszlai3 · Gergely Szakács1,5 Received: 30 November 2018 / Revised: 9 April 2019 / Accepted: 11 April 2019 © The Author(s) 2019 Abstract ABCB6 belongs to the family of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intra-cellular membranes, bearing signifcant impact on human disease and pharmacology. Although mutations in the ABCB6 gene have been linked to a variety of pathophysiological conditions ranging from transfusion incompatibility to pigmentation defects, its precise cellular localization and function is not understood. In particular, the intracellular localiza- tion of ABCB6 has been a matter of debate, with conficting reports suggesting mitochondrial or endolysosomal expres- sion. ABCB6 shows signifcant sequence identity to HMT-1 (heavy metal tolerance factor 1) proteins, whose evolutionarily conserved role is to confer tolerance to heavy metals through the intracellular sequestration of metal complexes. Here, we show that the cadmium-sensitive phenotype of Schizosaccharomyces pombe and Caenorhabditis elegans strains defective for HMT-1 is rescued by the human ABCB6 protein. Overexpression of ABCB6 conferred tolerance to cadmium and As(III) (As2O3), but not to As(V) (Na2HAsO4), Sb(V), Hg(II), or Zn(II). Inactivating mutations of ABCB6 abolished vacuolar sequestration of cadmium, efectively suppressing the cadmium tolerance phenotype. Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity. Our fndings reveal ABCB6 as a functional homologue of the HMT-1 proteins, linking endolysosomal ABCB6 to the highly conserved mechanism of intracellular cadmium detoxifcation. Keywords ABC transporters · Subcellular localization · ABCB6 · HMT-1 · Endolysosomal system · Detoxifcation · Cadmium Introduction Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0001 8-019-03105 -5) contains supplementary material, which is available to authorized users. ATP-binding cassette (ABC) transporters constitute one of the largest protein families in prokaryotes and eukary- * Gergely Szakács otes. ABC transporters are integral transmembrane proteins [email protected] that function as active transporters, channels or regula- 1 Institute of Enzymology, Research Centre for Natural tors. Active ABC transporters harness the energy of ATP Sciences, Hungarian Academy of Sciences, Budapest, to move a diverse array of substrates in or out of cells, or Hungary into cellular vesicles. There are 48 human ABC transporters, 2 Department of Genetics, Institute of Biology, Eötvös Loránd many of which are linked to severe inherited diseases, such University, Budapest, Hungary as cystic fbrosis, or X-linked adrenoleukodystrophy [1]. 3 Department of Analytical Chemistry, Institute of Chemistry, Whereas several human ABC transporters have dedicated Eötvös Loránd University, Budapest, Hungary physiological roles (e.g., transport of phosphatidylcholine 4 Institute for Solid State Physics and Optics, Wigner Research by ABCB4/MDR3; antigen processing by ABCB2/3), most Centre for Physics, Hungarian Academy of Sciences, recognize various xenobiotics and contribute to the “chemo- Budapest, Hungary immunity” network of cells and organisms [2]. At the cel- 5 Department of Medicine I, Comprehensive Cancer Center, lular level, multidrug resistance (MDR) transporters such as Institute of Cancer Research, Medical University of Vienna, P-glycoprotein (ABCB1) play an important role in cancer Vienna, Austria Vol.:(0123456789)1 3 Z. Rakvács et al. drug resistance by reducing the concentration of chemother- sensitivity phenotype of HMT-1-defcient S. pombe and C. apeutics below a cell-killing threshold. In addition, MDR elegans strains. Our fndings reveal ABCB6 as a functional transporters are also expressed in pharmacological barriers orthologue of the HMT-1 proteins, linking ABCB6 to the such as the blood–brain barrier, where they modulate the highly conserved mechanism of intracellular cadmium passage of drugs [3]. detoxifcation. Consistent with our previous fndings show- ABCB6 is widely expressed in many tissues, especially in ing extramitochondrial localization, these results provide the heart, liver, skeletal muscles [4], the red blood cells [5, functional evidence supporting the endolysosomal function 6], and skin [7]. ABCB6 is a half transporter of 842 amino of ABCB6. acids, containing a unique N-terminal region followed by the ABC core consisting of a transmembrane domain and a cyto- plasmic nucleotide-binding domain. ABCB6 forms homodi- Results mers [8, 9] and was shown to possess ATPase and transport activities after purifcation and functional reconstitution into Heterologous expression of human ABCB6 restores liposomes [10]. At present, the subcellular localization of cadmium tolerance of S. pombe hmt‑1Δ mutants ABCB6 remains a matter of debate. In 2006, ABCB6 was described as a mitochondrial porphyrin transporter with an To test whether ABCB6 and SpHMT-1 have overlapping essential role in heme biosynthesis [8]. Subsequent studies functions, we expressed the wild-type human ABCB6 pro- have found ABCB6 to be dispensable for erythropoiesis [5, tein, a catalytically inactive mutant variant (ABCB6-KM 9], suggesting that mitochondrial porphyrin import may not [9]) and SpHMT-1 in a hmt-1-deleted mutant S. pombe depend on ABCB6. In addition, several research groups have strain showing increased cadmium (Cd) sensitivity (Fig. 1a). identifed ABCB6 in extramitochondrial compartments, SpHMT-1-GFP was also localized to the vacuoles, matching challenging the paradigm linking the expression and func- the staining of the vacuolar membrane by FM 4–64 [22]. tion of ABCB6 to mitochondria. ABCB6 was detected in the Confocal microscopy analysis of cells expressing ABCB6- plasma membrane of cells [11], the red blood cell membrane GFP or SpHMT-1-GFP revealed a similar intracellular pat- [5, 9], melanosomes [12] and throughout the endolysosomal tern, indicating that the human ABCB6 protein is targeted continuum [13–17]. However, the physiological function of to the yeast vacuoles (Fig. 1b). As expected, expression of ABCB6 in the endolysosomal compartment has remained SpHMT-1 fully eliminated the increased cadmium sensitiv- elusive. ity of the hmt-1Δ mutant strain. Expression of wild-type ABCB6 exhibits topological and sequential similarity to ABCB6 also restored cadmium tolerance, allowing trans- HMT (Heavy Metal Tolerance) family proteins (Supplemen- formed S. pombe colonies to grow in the presence of Cd(II) tary Table 1). HMT-1 proteins in fssion yeast (Schizosac- (Fig. 1c, Supplementary Figure 1). Rescue of hmt-1-deleted charomyces pombe), nematode (Caenorhabditis elegans) strains depended on the functionality of the heterologously and the fruit fy (Drosophila melanogaster) fulfll a con- expressed transporter, since an inactivating mutation afect- served role in conferring heavy metal resistance [18–21]. ing a conserved Walker A lysine of ABCB6 prevented the In fssion yeast, SpHMT-1 mediates the vacuolar sequestra- growth of hmt-1-deleted colonies in the presence of cad- tion of metal adducts including phytochelatin, glutathione mium. Rescue was also observed in liquid medium (Fig. 1d). or metallothionein complexes of heavy metal ions [18]. Cytotoxicity assays revealed that the expression of ABCB6 An elegant study from the Vatamaniuk laboratory has shown in hmt-1Δ S. pombe cells conferred resistance to As(III), that HMT-1 proteins in C. elegans (CeHMT-1) and D. mela- but not to As(V), Sb(V), Hg(II), or Zn(II) (Supplementary nogaster (DmHMT-1) can also mediate the sequestration Figure 2). and elimination of Cd complexes. In particular, heterolo- gously expressed DmHMT-1 or CeHMT-1 were shown to Determination of vacuolar cadmium content suppress the cadmium hypersensitivity of S. pombe hmt-1 mutants, concomitant with the localization of CeHMT-1 SpHMT-1 reduces the intracellular concentrations of cad- to the vacuolar membrane. These results clearly indicated mium by catalyzing the vacuolar sequestration of Cd–PC that the HMT-1-mediated detoxifcation of heavy metals complexes [18]. To verify that the ability of ABCB6 to is preserved during evolution, extending to some inverte- suppress the Cd hypersensitivity of HMT-1-deficient S. brate species lacking the ability to synthesize phytochelatin pombe mutants relies on an orthologous function, we (PC) [20, 21]. Given the similarity of HMT-1 and ABCB6 assayed the Cd contents of intact vacuoles isolated from sequences, the major aim of this study was to test if ABCB6 CdCl2-treated yeast cells. The integrity of the purified can complement the function of HMT-1 proteins. We show vacuoles was confirmed by acridine-orange (AO) stain- that ABCB6 can be functionally expressed in the vacuolar/ ing (Supplementary Figure 3). Graphite furnace atomic endosomal membrane, resulting in a rescue of the cadmium absorption spectrometry (GFAAS) analysis showed 1 3 The human ABCB6 protein is the functional homologue of HMT-1 proteins mediating cadmium… a 1. 2. 3. 4. 5. 130 kDa 100 kDa
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