School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK
J Cell Sci. 2020 Aug 25;133(16):jcs249201. doi: 10.1242/jcs.249201.
The concentration of essential micronutrients, such as copper (used here to describe both Cu and Cu), 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.
必需微量营养素（如铜（这里用于描述 Cu 和 Cu））在细胞内的浓度受到严格调节，以避免其缺乏和毒性作用。在内体溶酶体网络中，通过逆行介导的营养转运体的分拣和再循环是调节营养平衡的一个重要过程。细胞内铜稳态主要由两种转运体调节：铜输入转运体铜转运蛋白 1（CTR1；也称为 SLC31A1），控制铜的摄取，以及铜外排 ATP 酶 ATP7A，这是公认的逆行货物。在这里，我们表明，在响应不断变化的细胞外铜时，逆行控制 CTR1 向细胞表面的传递。在铜暴露后，CTR1 被内吞以防止过多的铜摄取。我们揭示了内化的 CTR1 定位于逆行阳性内体上，并且在细胞外铜减少时，逆行控制 CTR1 回收到细胞表面以维持铜稳态。除了铜之外，CTR1 在铂的运输中也起着核心作用。基于铂的癌症药物的疗效与 CTR1 的表达相关。与此一致，我们证明了逆行缺陷细胞对基于铂的药物顺铂的敏感性降低。
