Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 27, Pages 13905-13916Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.731281
Keywords
copper transport; cysteine protease; intracellular processing; metal homeostasis; protein processing; anti-cancer drug; cathepsin; cisplatin
Categories
Funding
- National Institutes of Health [DK074192]
- Alexander and Margaret Stewart Trust from Duke University Cancer Institute
- Swedish Research Council [524-2014-1]
- Ake Wiberg Foundation [M14-0080]
- Magnus Bergvall Foundation [2014-00058]
- Deutsche Forschungsgemeinschaft [Re1584/6-1, SFB850]
- Excellence Initiative of the German Federal and State Governments [EXC 294]
- Slovene Research Agency [P1-0140]
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Copper is an essential metal ion for embryonic development, iron acquisition, cardiac function, neuropeptide biogenesis, and other critical physiological processes. Ctr1 is a high affinity Cu+ transporter on the plasma membrane and endosomes that exists as a full-length protein and a truncated form of Ctr1 lacking the methionine- and histidine-rich metal-binding ectodomain, and it exhibits reduced Cu+ transport activity. Here, we identify the cathepsin L/B endolysosomal proteases functioning in a direct and rate-limiting step in the Ctr1 ectodomain cleavage. Cells and mice lacking cathepsin L accumulate full-length Ctr1 and hyper-accumulate copper. As Ctr1 also transports the chemotherapeutic drug cisplatin via direct binding to the ectodomain, we demonstrate that the combination of cisplatin with a cathepsin L/B inhibitor enhances cisplatin uptake and cell killing. These studies identify a new processing event and the key protease that cleaves the Ctr1 metal-binding ectodomain, which functions to regulate cellular Cu+ and cisplatin acquisition.
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