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

Zsófia Rakvács, Nóra Kucsma, Melinda Gera, Barbara Igriczi, Katalin Kiss, János Barna, Dániel Kovács, T. Vellai, László Bencs, Johannes M. Reisecker, N. Szoboszlai, G. Szakács

Research output: Contribution to journalArticle

1 Citation (Scopus)

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) (As 2 O 3 ), but not to As(V) (Na 2 HAsO 4 ), 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.

Original languageEnglish
JournalCellular and Molecular Life Sciences
DOIs
Publication statusPublished - Jan 1 2019

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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