Abstract
ABSTRACTCopper, a transition metal, is an essential component for normal growth and development. It acts as a critical co-factor of many enzymes that play key roles in diverse cellular processes. The present study attempts to investigate the regulatory functions decisively controlling copper trafficking during development and aging of the Drosophila model system. Hence, through engagement of the GAL4/UAS genetic platform and RNAi technology, we herein examined the in vivo significance of Atox1 and CCS genes, products of which pivotally govern cellular copper trafficking in fly tissue pathophysiology. Specifically, we analyzed the systemic effects of their targeted downregulation on the eye, wing, neuronal cell populations and whole-body tissues of the fly. Our results reveal that, in contrast to the eye, suppression of their expression in the wing leads to a notable increase in the percentage of malformed organs observed. Furthermore, we show that Atox1 or CCS gene silencing in either neuronal or whole-body tissues can critically affect the viability and climbing capacity of transgenic flies, while their double-genetic targeting suggests a rather synergistic mode of action of the cognate protein products. Interestingly, pharmacological intervention with the anti-cancer drug cisplatin indicates the major contribution of CCS copper chaperone to cisplatin's cellular trafficking, and presumably to tumor resistance often acquired during chemotherapy. Altogether, it seems that Atox1 and CCS proteins serve as tissue/organ-specific principal regulators of physiological Drosophila development and aging, while their tissue-dependent downregulation can provide important insights for Atox1 and CCS potential exploitation as predictive gene biomarkers of cancer-cell chemotherapy responses.
Highlights
The maintenance of metal homeostasis in cells is an issue of major importance for an organism’s proper function and well-being
Copper homeostasis is preserved via the activity of copper transporters involved in metal uptake and export from cells, and copper chaperones that deliver it to specific targets in the cell (Bertinato and L’Abbe, 2004)
Copper trafficking that depends on chaperones is an evolutionary conserved process The Clustal Omega-mediated alignment in between human (Homo sapiens) and fly (D. melanogaster) Atox1 proteins reveals a strong homology in their amino acid sequences, with a remarkable conservation of the ‘MxCxxC’ motif (Fig. 1A), which has been previously reported to serve as a critical site for copper binding (Wernimont et al, 2000; Boal and Rosenzweig, 2009a,b; Matson Dzebo et al, 2016; Kardos et al, 2018)
Summary
The maintenance of metal homeostasis in cells is an issue of major importance for an organism’s proper function and well-being. We have examined the in vivo role of the two major copper-trafficking chaperones, Atox1 and CCS, during fly development and aging by virtue of their tissue-specific downregulation.
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