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

Zsófia Rakvács¹, Nóra Kucsma¹, Melinda Gera¹

¹Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.

Cellular and Molecular Life Sciences : CMLS

|May 5, 2019

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.

Insights

Human ABCB6 protein functions in heavy metal detoxification, particularly for cadmium. This research links ABCB6 to the conserved mechanism of intracellular cadmium sequestration and tolerance.

Area of Science:

Biochemistry
Molecular Biology
Cell Biology

Background:

ATP-binding cassette (ABC) transporters play crucial roles in cellular transport and are implicated in human diseases.
The exact cellular localization and function of ABCB6, an ABC transporter, remain unclear, with conflicting evidence regarding its presence in mitochondria or endolysosomes.
ABCB6 shares sequence identity with heavy metal tolerance (HMT-1) proteins, suggesting a role in heavy metal resistance.

Purpose of the Study:

To elucidate the cellular function and localization of the human ABCB6 transporter.
To determine if ABCB6 functions as a heavy metal transporter, similar to HMT-1 proteins.
To investigate the role of ABCB6 in cadmium detoxification and its cellular mechanisms.

Main Methods:

Functional rescue assays using yeast (Schizosaccharomyces pombe) and worm (Caenorhabditis elegans) models with ABCB6.
Phenotypic analysis of ABCB6 overexpression and inactivating mutations in response to various heavy metals.
Assessment of cadmium sequestration in vacuoles upon modulation of ABCB6 expression in human glioblastoma cells.

Main Results:

Human ABCB6 rescued the cadmium-sensitive phenotype in HMT-1 deficient yeast and worm strains.
ABCB6 overexpression conferred tolerance to cadmium and Arsenic(III), but not to other tested metals.
Inactivating ABCB6 mutations abolished vacuolar cadmium sequestration and cadmium tolerance.
Altered ABCB6 expression levels in human cells directly correlated with changes in cadmium sensitivity.

Conclusions:

ABCB6 is a functional homologue of HMT-1 proteins, playing a conserved role in heavy metal detoxification.
Endolysosomal ABCB6 is involved in the intracellular sequestration and detoxification of cadmium.
ABCB6 represents a key component in the cellular defense mechanism against cadmium toxicity.

Read full analysis

Keywords:

ABC transporters ABCB6 Cadmium Detoxification Endolysosomal system HMT-1 Subcellular localization

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