The human ABCB6 protein is the functional homologue of HMT-1 proteins mediating cadmium detoxification

Abstract

ABCB6 belongs to the family of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intra-cellular membranes, bearing significant 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 localization of ABCB6 has been a matter of debate, with conflicting reports suggesting mitochondrial or endolysosomal expression. ABCB6 shows significant 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, effectively suppressing the cadmium tolerance phenotype. Modulation of ABCB6 expression levels in human glioblastoma cells resulted in a concomitant change in cadmium sensitivity. Our findings reveal ABCB6 as a functional homologue of the HMT-1 proteins, linking endolysosomal ABCB6 to the highly conserved mechanism of intracellular cadmium detoxification.Electronic supplementary materialThe online version of this article (10.1007/s00018-019-03105-5) contains supplementary material, which is available to authorized users.

Cryo‐electron microscopy structure of human ABCB6 transporter

“…ATP‐driven translocation of porphyrin into mitochondria is severely impaired in the absence of ABCB6, 5 highlighting the role of ABCB6 in heme precursor translocation. Several studies have suggested that ABCB6 is also presented in other membrane systems like intracellular endo/lysosomal compartment 6–9 or the plasma membrane, 10 which is consistent with its ability to confer tolerance to toxic heavy metals 1,3 . ABCB6 has also been shown to protect cells from oxidative stress 11 and drug toxicity 12,13 .…”

“…ATP-binding cassette transporter 6 of subfamily B (ABCB6) is a widely expressed ABC transporter that has been found in many tissues, especially in liver, muscle, red blood cells (RBCs), and skin. 1 It was originally isolated from liver by screening P-glycoprotein-like genes related to drug resistance. 2 Sequence analysis indicates that ABCB6 is a human functional homologue of heavy metal tolerance factor 1.…”

“…Several studies have suggested that ABCB6 is also presented in other membrane systems like intracellular endo/lysosomal compartment [6][7][8][9] or the plasma membrane, 10 which is consistent with its ability to confer tolerance to toxic heavy metals. 1,3 ABCB6 has also been shown to protect cells from oxidative stress 11 and drug toxicity. 12,13 The overexpression of ABCB6 enhances drug resistance against the antineoplastic drug SN-38 and vincristine, suggesting that the transporter is a potential anti-cancer therapeutic target.…”

Aberrant DNA Methylation of ABC Transporters in Cancer

“…ABCB6 is involved in porphyrin transport and iron homeostasis [ 94 ]. It is widely expressed in the heart, liver, skeletal muscles, red blood cells, and the skin [ 95 ].…”

An inventory of lysosomal ABC transporters

“…Our own laboratory has failed to detect ABCB6 in the mitochondria, regardless of the cellular or experimental models. As opposed to ABCB7/8/10, which showed the expected mitochondrial expression pattern, endogenous or cDNA‐derived ABCB6 was consistently localized in extramitochondrial compartments by confocal or electron microscopy, and could be no longer found in pure mitochondrial fractions devoid of lysosomal contamination [107,105,108,87,109].…”