scholarly journals The Mitochondrial Metallochaperone SCO1 Is Required to Sustain Expression of the High-Affinity Copper Transporter CTR1 and Preserve Copper Homeostasis

Cell Reports ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. 933-943 ◽  
Author(s):  
Christopher J. Hlynialuk ◽  
Binbing Ling ◽  
Zakery N. Baker ◽  
Paul A. Cobine ◽  
Lisa D. Yu ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Copper Transporter ◽  
High Affinity

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

2020 ◽  
Vol 133 (16) ◽  
pp. jcs249201 ◽  
Author(s):  
Rachel Curnock ◽  
Peter J. Cullen
Keyword(s):  
Cell Surface ◽  
Nutrient Balance ◽  
Copper Homeostasis ◽  
Copper Exposure ◽  
Copper Uptake ◽  
Copper Transporter ◽  
High Affinity ◽  
Cellular Copper ◽  
Copper Transporter 1 ◽  
Toxicity Effects

ABSTRACTThe 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.

scholarly journals Autonomous requirements of the Menkes disease protein in the nervous system

2015 ◽  
Vol 309 (10) ◽  
pp. C660-C668 ◽  
Author(s):  
Victoria L. Hodgkinson ◽  
Sha Zhu ◽  
Yanfang Wang ◽  
Erik Ladomersky ◽  
Karen Nickelson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Copper Deficiency ◽  
Copper Homeostasis ◽  
Signs And Symptoms ◽  
Menkes Disease ◽  
Copper Transporter ◽  
Sensorimotor Deficits ◽  
The Central Nervous System

Menkes disease is a fatal neurodegenerative disorder arising from a systemic copper deficiency caused by loss-of-function mutations in a ubiquitously expressed copper transporter, ATP7A. Although this disorder reveals an essential role for copper in the developing human nervous system, the role of ATP7A in the pathogenesis of signs and symptoms in affected patients, including severe mental retardation, ataxia, and excitotoxic seizures, remains unknown. To directly examine the role of ATP7A within the central nervous system, we generated Atp7a Nes mice, in which the Atp7a gene was specifically deleted within neural and glial cell precursors without impairing systemic copper homeostasis, and compared these mice with the mottled brindle ( mo-br) mutant, a murine model of Menkes disease in which Atp7a is defective in all cells. Whereas mo-br mice displayed neurodegeneration, demyelination, and 100% mortality prior to weaning, the Atp7a Nes mice showed none of these phenotypes, exhibiting only mild sensorimotor deficits, increased anxiety, and susceptibility to NMDA-induced seizure. Our results indicate that the pathophysiology of severe neurological signs and symptoms in Menkes disease is the result of copper deficiency within the central nervous system secondary to impaired systemic copper homeostasis and does not arise from an intrinsic lack of ATP7A within the developing brain. Furthermore, the sensorimotor deficits, hypophagia, anxiety, and sensitivity to NMDA-induced seizure in the Atp7a Nes mice reveal unique autonomous requirements for ATP7A in the nervous system. Taken together, these data reveal essential roles for copper acquisition in the central nervous system in early development and suggest novel therapeutic approaches in affected patients.

scholarly journals Regulation of murine copper homeostasis by members of the COMMD protein family

2020 ◽  
Vol 14 (1) ◽  
pp. dmm045963
Author(s):  
Amika Singla ◽  
Qing Chen ◽  
Kohei Suzuki ◽  
Jie Song ◽  
Alina Fedoseienko ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Copper Accumulation ◽  
Copper Transporter ◽  
Copper Excretion ◽  
Copper Absorption ◽  
Hepatic Copper ◽  
High Copper ◽  
Molecular Machinery ◽  
And Function

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.

scholarly journals Essential Roles in Development and Pigmentation for the Drosophila Copper Transporter DmATP7

2006 ◽  
Vol 17 (1) ◽  
pp. 475-484 ◽  
Author(s):  
Melanie Norgate ◽  
Esther Lee ◽  
Adam Southon ◽  
Ashley Farlow ◽  
Philip Batterham ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Cellular Level ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Copper Transporter ◽  
Disease Phenotypes ◽  
In Vivo Analysis ◽  
Cellular Copper ◽  
P Type

Defects in the mammalian Menkes and Wilson copper transporting P-type ATPases cause severe copper homeostasis disease phenotypes in humans. Here, we find that DmATP7, the sole Drosophila orthologue of the Menkes and Wilson genes, is vital for uptake of copper in vivo. Analysis of a DmATP7 loss-of-function allele shows that DmATP7 is essential in embryogenesis, early larval development, and adult pigmentation and is probably required for copper uptake from the diet. These phenotypes are analogous to those caused by mutation in the mouse and human Menkes genes, suggesting that like Menkes, DmATP7 plays at least two roles at the cellular level: delivering copper to cuproenzymes required for pigmentation and neuronal function and removing excess cellular copper via facilitated efflux. DmATP7 displays a dynamic and unexpected expression pattern in the developing embryo, implying novel functions for this copper pump and the lethality observed in DmATP7 mutant flies is the earliest seen for any copper homeostasis gene.

scholarly journals Laccases Involved in 1,8-Dihydroxynaphthalene Melanin Biosynthesis in Aspergillus fumigatus Are Regulated by Developmental Factors and Copper Homeostasis

2013 ◽  
Vol 12 (12) ◽  
pp. 1641-1652 ◽  
Author(s):  
Srijana Upadhyay ◽  
Guadalupe Torres ◽  
Xiaorong Lin
Keyword(s):  
Immune Responses ◽  
Aspergillus Fumigatus ◽  
Gene Cluster ◽  
Gene Expression Pattern ◽  
Copper Homeostasis ◽  
Copper Level ◽  
Fungal Virulence ◽  
Copper Transporter ◽  
Melanin Biosynthesis ◽  
Content Type

ABSTRACTAspergillus fumigatusproduces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster inA. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression ofA. fumigatuslaccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction ofabr1andabr2, a response similar to that induced by copper starvation. Furthermore, nonpigmentedctpAΔ conidia elicited much stronger immune responses from the infected invertebrate hostGalleria mellonellathan the pigmentedctpAΔ or wild-type conidia. Such enhancement in elicitingGalleriaimmune responses was independent of thectpAΔ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.

scholarly journals High-Affinity Copper Transport and Snq2 Export Permease of Saccharomyces cerevisiae Modulate Cytotoxicity of PR-10 from Theobroma cacao

2009 ◽  
Vol 22 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Cristina Pungartnik ◽  
Aline Clara da Silva ◽  
Sarah Alves de Melo ◽  
Karina Peres Gramacho ◽  
Júlio Cézar de Mattos Cascardo ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Theobroma Cacao ◽  
Single Gene ◽  
Copper Transport ◽  
Amino Acid Sequences ◽  
Yeast Cells ◽  
Antioxidant Defenses ◽  
Copper Transporter ◽  
High Affinity ◽  
Yeast Mutants

A pathogenesis-related (PR) protein from Theobroma cacao (TcPR-10) was identified from a cacao–Moniliophthora perniciosa interaction cDNA library. Nucleotide and amino acid sequences showed homology with other PR-10 proteins having P loop motif and Betv1 domain. Recombinant TcPR-10 showed in vitro and in vivo ribonuclease activity, and antifungal activity against the basidiomycete cacao pathogen M. perniciosa and the yeast Saccharomyces cerevisiae. Fluorescein isothiocyanate-labeled TcPR-10 was internalized by M. perniciosa hyphae and S. cerevisiae cells and inhibited growth of both fungi. Energy and temperature-dependent internalization of the TcPR-10 suggested an active importation into the fungal cells. Chronical exposure to TcPR-10 of 29 yeast mutants with single gene defects in DNA repair, general membrane transport, metal transport, and antioxidant defenses was tested. Two yeast mutants were hyperresistant compared with their respective isogenic wild type: ctr3Δ mutant, lacking the high-affinity plasma membrane copper transporter and mac1Δ, the copper-sensing transcription factor involved in regulation of high-affinity copper transport. Acute exposure of exponentially growing yeast cells revealed that TcPR-10 resistance is also enhanced in the Snq2 export permease-lacking mutant which has reduced intracellular presence of TcPR-10.

The CaCTR1 gene is required for high-affinity iron uptake and is transcriptionally controlled by a copper-sensing transactivator encoded by CaMAC1

Microbiology ◽  
2004 ◽  
Vol 150 (7) ◽  
pp. 2197-2208 ◽  
Author(s):  
Marcus E. Marvin ◽  
Robert P. Mason ◽  
Annette M. Cashmore
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Iron Uptake ◽  
Invasive Growth ◽  
Hostile Environment ◽  
Null Mutant ◽  
Copper Uptake ◽  
Similar System ◽  
Copper Transporter ◽  
High Affinity ◽  
Null Strain

The ability of Candida albicans to acquire iron from the hostile environment of the host is known to be necessary for virulence and appears to be achieved using a similar system to that described for Saccharomyces cerevisiae. In S. cerevisiae, high-affinity iron uptake is dependent upon the acquisition of copper. The authors have previously identified a C. albicans gene (CaCTR1) that encodes a copper transporter. Deletion of this gene results in a mutant strain that grows predominantly as pseudohyphae and displays aberrant morphology in low-copper conditions. This paper demonstrates that invasive growth by C. albicans is induced by low-copper conditions and that this is augmented in a Cactr1-null strain. It also shows that deletion of CaCTR1 results in defective iron uptake. In S. cerevisiae, genes that facilitate high-affinity copper uptake are controlled by a copper-sensing transactivator, ScMac1p. The authors have now identified a C. albicans gene (CaMAC1) that encodes a copper-sensing transactivator. A Camac1-null mutant displays phenotypes similar to those of a Cactr1-null mutant and has no detectable CaCTR1 transcripts in low-copper conditions. It is proposed that high-affinity copper uptake by C. albicans is necessary for reductive iron uptake and is transcriptionally controlled by CaMac1p in a similar manner to that in S. cerevisiae.

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