Smith Ann, Rish Kimberly R, Lovelace Rachel, Hackney Jennifer F, Helston Rachel M
Division of Molecular Biology & Biochemistry, School of Biological Sciences, University of Missouri-K.C., 5007 Rockhill Road, Kansas City, MO 64110, USA.
Biometals. 2009 Jun;22(3):421-37. doi: 10.1007/s10534-008-9178-z. Epub 2008 Nov 28.
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 both hmox1 and mt1 is 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 for hmox1 transcription, while cytosolic copper and CCS1 provide a link for the known simultaneous regulation of hmox1 and mt1 by heme-HPX.
血红素结合蛋白（HPX）能紧密结合血红素，从而在溶血、创伤和缺血再灌注损伤期间保护细胞免受血红素毒性的影响。通过血红素-HPX的内吞作用摄取血红素，随后由血红素加氧酶-1（HMOX1）进行血红素分解代谢，可增加调节性铁池，从而将血红素代谢与铁代谢联系起来。正常的铁稳态需要细胞富含铜。当血红素-HPX诱导HMOX1时，储存铜的金属硫蛋白（MTs）也会被诱导，而将铜输送到铜锌超氧化物歧化酶（CCS1）的铜反应性铜伴侣蛋白则会减少；当细胞内铜水平升高时，这两种情况都是已知的反应。需要血红素-HPX的内吞作用来调节CCS1，因为信号配体钴原卟啉（CoPP）-HPX虽然不诱导HMOX1，但确实与血红素-HPX在内体中共定位，也会降低CCS1。这些观察结果支持血红素-HPX在细胞中调动铜的作用。铜螯合剂 bathocuproinedisulfonate（BCDS）可阻止hmox1和mt1的调节，但不会阻止血红素- AlexaFluor标记的HPX摄取到内体中。支持铜在血红素-HPX对HMOX1调节中发挥作用的是，由四乙烯五胺或四胺产生的营养性铜缺乏会阻止HMOX1的诱导。利用模拟成熟内体的条件，我们发现铜可防止血红素重新结合到脱辅基HPX上。本文提出了一个模型，其中铜的内吞作用与血红素-HPX的内吞作用一起提供了一种促进血红素在成熟内体中从HPX输出的方式：hmox1转录需要血红素，而细胞质中的铜和CCS1为血红素-HPX对hmox1和mt1的已知同时调节提供了联系。
