Cathepsin Protease Controls Copper and Cisplatin Accumulation via Cleavage of the Ctr1 Metal-binding Ectodomain.
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.
['Öhrvik|Helena|H|', 'Logeman|Brandon|B|', 'Turk|Boris|B|', 'Reinheckel|Thomas|T|', 'Thiele|Dennis J|DJ|']
D000595:Amino Acid Sequence D000818:Animals D002403:Cathepsins D027682:Cation Transport Proteins D002460:Cell Line D002945:Cisplatin D003300:Copper D000079923:Copper Transporter 1 D006801:Humans D051379:Mice D018345:Mice, Knockout D059748:Proteolysis D017386:Sequence Homology, Amino Acid
cathepsin cisplatin anti-cancer drug copper transport cysteine protease intracellular processing metal homeostasis protein processing