Mammalian copper homeostasis requires retromer-dependent recycling of the high-affinity copper transporter 1 (CTR1/SLC31A1)

BioRxiv : the Preprint Server for Biology
R. Curnock, Peter J Cullen

Abstract

The mammalian cell surface is decorated with a plethora of integral membrane proteins including those required for the transport of micronutrients, such as copper, which are essential to cellular health. The concentration of micronutrients within the cell is tightly regulated to avoid their adverse deficiency and toxicity effects. The sorting and recycling of nutrients transporters within the endo-lysosomal network is recognised as an essential process in regulating nutrient balance. The evolutionarily conserved endosomal sorting complex, retromer, coordinates integral membrane protein recognition and retrieval. Cellular copper homeostasis is regulated primarily by two transporters: the major copper influx transporter copper transporter 1 (CTR1/SLC31A1), which controls the uptake of copper from the extracellular environment and is essential for early embryonic development, and the established retromer cargo, the copper-transporting ATPase, ATP7A. Here, we show that in response to fluctuating extracellular copper the retromer complex 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 ...Continue Reading

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