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Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1

Curnock, Rachel, Cullen, Peter J.·2020·Journal of Cell Science

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Abstract

The concentration of essential micronutrients, such as copper (used here to describe both Cu+ and Cu2+), within the cell is tightly regulated to avoid their adverse deficiency and toxicity effects. Retromer-mediated sorting and recycling of nutrient transporters within the endo-lysosomal network is an essential process in regulating nutrient balance. Cellular copper homeostasis is regulated primarily by two transporters: the copper influx transporter copper transporter 1 (CTR1; also known as SLC31A1), which controls the uptake of copper, and the copper-extruding ATPase ATP7A, a recognised retromer cargo. Here, we show that in response to fluctuating extracellular copper, retromer controls the delivery of CTR1 to the cell surface. Following copper exposure, CTR1 is endocytosed to prevent excessive copper uptake. We reveal that internalised CTR1 localises on retromer-positive endosomes and, in response to decreased extracellular copper, retromer controls the recycling of CTR1 back to the cell surface to maintain copper homeostasis. In addition to copper, CTR1 plays a central role in the trafficking of platinum. The efficacy of platinum-based cancer drugs has been correlated with CTR1 expression. Consistent with this, we demonstrate that retromer-deficient cells show reduced sensitivity to the platinum-based drug cisplatin.

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  • Expression of dominant negative RAB10(T23N) in wild-type HeLa cells reduced steady-state surface levels of Retromer cargoes GLUT1, KIDINS220, and the copper-dependent cell surface recycling of CTR1.

    “Finally, we lentivirally expressed dominant negative RAB10(T23N) in wild-type HeLa cells. This revealed a reduced steady-state surface level of Retromer cargoes GLUT1, KIDINS220 and the copper-dependent cell surface recycling of CTR1108 (Fig. 5E, F).”

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Metadata

Authors
Curnock, R., & Cullen, P. J.
Affiliations
School of Biochemistry , Biomedical Sciences Building , , Bristol BS8 1TD , UK
Venue
Journal of Cell Science
Published
2020-08-15
Volume
133
Issue
16
ISSN
  • 1477-9137
  • 0021-9533
Cited by
60
References
3
Language
en
Funders
  • Medical Research Council (MR/P018807/1)
  • Wellcome Trust (104568/Z/14/Z)
  • Lister Institute of Preventive Medicine

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