Role for copper in the cellular and regulatory effects of heme-hemopexin.
Role for copper in the cellular and regulatory effects of heme-hemopexin.
复制标题
铜在血红素-血红素结合蛋白的细胞和调节作用中的作用。
DOI：
10.1007/s10534-008-9178-z
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Helston,RachelM
中科院分区：
文献类型：
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作者：
Smith,Ann;Rish,KimberlyR;Lovelace,Rachel;Hackney,JenniferF;Helston,RachelM
血红素（HPX）与血红素紧密结合，从而保护细胞在溶血、创伤和缺血再灌注损伤时免受血红素毒性的影响。通过血红素- hpx的内吞作用和血红素氧合酶-1 （HMOX1）的血红素分解代谢，血红素摄取增加了调节性铁池，从而将血红素代谢与铁代谢联系起来。正常的铁稳态需要含铜充足的细胞。当血红素- hpx诱导HMOX1时，铜储存金属硫蛋白（MTs）也被诱导，而向Cu， Zn超氧化物歧化酶（CCS1）递送铜的铜响应性伴侣蛋白（copper-responsive copper chaperone）减少；当细胞中的铜含量升高时，这两种反应都是已知的。由于信号配体钴原卟啉(CoPP)-HPX不会诱导HMOX1，但在核内体中与血红素-HPX共定位，也会降低CCS1，因此需要血红素-HPX的内噬作用来调节CCS1。这些观察结果支持血红素- hpx在细胞中动员铜。铜螯合剂-二磺酸盐（BCDS）可阻止thhmox1和mt1的调节，但不能将血红素- alexafluor标记的HPX摄取到内体中。支持铜在血红素- hpx调控HMOX1中的作用，四乙烯五胺或232四胺引起的营养铜缺乏阻止了HMOX1的诱导。利用模拟成熟内体的条件，我们发现铜可以阻止血红素与载脂蛋白hpx的再结合。提出了一种模型，其中铜的内吞噬作用与血红素-HPX的内吞噬作用为成熟内体中HPX的血红素输出提供了一种手段：血红素是hmox1转录所需要的，而胞质铜和CCS1为已知的血红素-HPX同时调节hmox1和mt1提供了一种联系。
Hemopexin (HPX) binds heme tightly, thus protecting cells from heme toxicity during hemolysis, trauma and ischemia-reperfusion injury. Heme uptake via endocytosis of heme-HPX followed by heme catabolism by heme oxygenase-1 (HMOX1) raises regulatory iron pools, thus linking heme metabolism with that of iron. Normal iron homeostasis requires copper-replete cells. When heme-HPX induces HMOX1, the copper-storing metallothioneins (MTs) are also induced whereas the copper-responsive copper chaperone that delivers copper to Cu, Zn superoxide dismutase, CCS1, is decreased; both are known responses when cellular copper levels rise. Endocytosis of heme-HPX is needed to regulate CCS1 since the signaling ligand cobalt-protoporphyrin (CoPP)-HPX, which does not induce HMOX1 but does co-localize with heme-HPX in endosomes, also decreased CCS1. These observations support that heme-HPX mobilizes copper in cells. The regulation of bothhmox1andmt1is prevented by the copper-chelator, bathocuproinedisulfonate (BCDS), but not uptake of heme-AlexaFluor-labeled HPX into endosomes. Supporting a role for copper in HMOX1 regulation by heme-HPX, nutritional copper deficiency generated by tetraethylene pentamine or 232 tetraamine prevented HMOX1 induction. Using conditions that mimic maturing endosomes, we found that copper prevents rebinding of heme to apo-HPX. A model is presented in which copper endocytosis together with that of heme-HPX provides a means to facilitate heme export from HPX in the maturing endosomes: heme is needed forhmox1transcription, while cytosolic copper and CCS1 provide a link for the known simultaneous regulation ofhmox1andmt1by heme-HPX.