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Review
. 2021 Nov 1;134(21):jcs240523.
doi: 10.1242/jcs.240523. Epub 2021 Nov 4.

Dynamic and cell-specific transport networks for intracellular copper ions

Svetlana Lutsenko  1
Affiliations
Review

Dynamic and cell-specific transport networks for intracellular copper ions

Svetlana Lutsenko. J Cell Sci. .

Abstract

Copper (Cu) homeostasis is essential for the development and function of many organisms. In humans, Cu misbalance causes serious pathologies and has been observed in a growing number of diseases. This Review focuses on mammalian Cu(I) transporters and highlights recent studies on regulation of intracellular Cu fluxes. Cu is used by essential metabolic enzymes for their activity. These enzymes are located in various intracellular compartments and outside cells. When cells differentiate, or their metabolic state is otherwise altered, the need for Cu in different cell compartments change, and Cu has to be redistributed to accommodate these changes. The Cu transporters SLC31A1 (CTR1), SLC31A2 (CTR2), ATP7A and ATP7B regulate Cu content in cellular compartments and maintain Cu homeostasis. Increasing numbers of regulatory proteins have been shown to contribute to multifaceted regulation of these Cu transporters. It is becoming abundantly clear that the Cu transport networks are dynamic and cell specific. The comparison of the Cu transport machinery in the liver and intestine illustrates the distinct composition and dissimilar regulatory response of their Cu transporters to changing Cu levels.

Keywords: ATP7A; ATP7B; Copper; SLC31A1; SLC31A2; Transport.

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Conflict of interest statement

Competing interests I declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Sites of Cu utilization in a generalized cell and major Cu-handling proteins. (A) Cellular compartments in which Cu is used and respective cell functions. (B) Protein machinery involved in the Cu transport and regulation network. Cu enters the cells primarily through the high-affinity Cu transporter CTR1 but additional Cu-uptake mechanisms exist. In the cytosol, the Cu chaperones CCS, Atox1, and possibly Cox17 and Cox19 serve as compartment-specific Cu shuttles. The cytosolic redox environment, which is maintained by the glutathione pair (GSH:GSSG), influences the rate of Cu uptake via CTR1, as well as the oxidation state of Atox1. Cytosolic Cu-dependent SOD1 detoxify reactive oxygen species. Also in the cytosol, the Cu-sensing kinases ULK1, ULK2 and MEK1 regulate cell proliferation and autophagy, whereas the metallothioneins MT1, MT2, and MT3 bind to and store excess Cu. In the trans-Golgi network (TGN), the ATP-driven Cu transporters ATP7A and/or ATP7B receive Cu from Atox1 and activate the listed Cu-dependent enzymes. Glutaredoxin Grx1 regulates glutathionylation and Cu transfer to ATP7A. In mitochondria, Cu enables respiration and ATP production as a cofactor of cytochrome c oxidase (Cco). Secretory granules and specialized compartments such as melanosomes contain Cu-dependent enzymes, as well as Cu. Lysosomal Cu content is affected by the transporter SLC46A3. Cu-storage vesicles (CSVs) are cellular compartments with a very high Cu content. In the nucleus, histones H3-H4 act as Cu-dependent reductases, and Atox1 can be transiently found in the nucleus. CP, ceruloplasmin.
Fig. 2.
Fig. 2.
Cu-mediated regulation of the distribution of Cu transporters between cellular compartments. The amount of Cu taken into cells depends on the abundance of CTR1 at the plasma membrane. Excess Cu stimulates the clathrin- and dynamin-dependent endocytosis of CTR1. Atox1 removes Cu from the cytosolic-binding sites on CTR1 and also transfers Cu to the regulatory metal-binding sites on the ATP-driven Cu transporters ATP7A and ATP7B. From the recycling endosomes, CTR1 either returns to the plasma membrane with the assistance of retromer or moves to endo-lysosomes, where it interacts with the low-affinity Cu transporter CTR2 and regulates Cu release to the cytosol. Cu levels in the cytosol are maintained by the ATP-driven Cu transporters ATP7A and ATP7B. These transporters are typically targeted to sub-compartments of TGN but can also be found in endosomes and specialized compartments such as melanosomes. They transfer Cu from the cytosol to the TGN lumen to activate the Cu-dependent enzymes within the secretory pathway. When cytosolic Cu is high, ATP7A and ATP7B leave the TGN to facilitate Cu export (see Box 2 for details). Whether ATP7B and CTR2 move Cu in opposite direction in the same vesicular compartment is unclear.
Fig. 3.
Fig. 3.
A comparison of the Cu transport machinery and its response to Cu in enterocytes and hepatocytes. In enterocytes when Cu is limited, CTR1 is upregulated and can be found at the basolateral membrane and in vesicles in the vicinity to apical membrane. In low Cu, ATP7B is downregulated and is targeted to the TGN and endocytic vesicles. ATP7A is predominantly found in vesicles near the basolateral membrane. When Cu increases, intestinal CTR1 is downregulated, ATP7A relocates to the plasma membrane to facilitate Cu export. In response to Cu elevation, ATP7B is upregulated and ATP7B-containing vesicles become more numerous and larger in size. In hepatocytes, under basal or low Cu, CTR1 is targeted to the basolateral membranes and ATP7B is targeted predominantly to the TGN, where it delivers Cu to ceruloplasmin (CP). Cu elevation (in response to increased dietary intake or in Wilson disease) decreases CTR1 abundance at the plasma membrane via endocytosis or changes in the mRNA abundance. In high Cu, ATP7B levels do not change, instead ATP7B relocates to the endolysosomal compartment to facilitate Cu export.
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