Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity
Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity
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DOI：
10.1074/jbc.m114.607507
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发表时间：
2015-02-27
影响因子：
4.8
通讯作者：
Singh, Neena
中科院分区：
文献类型：
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作者：
Haldar, Swati;Tripathi, Ajai;Singh, Neena
脑内铁代谢紊乱是PrP疾病神经毒性的一个重要原因，PrPC是一组与PrPC从正常构象转变为聚集的PrP-scrapie(PrPSc)亚型相关的神经退行性疾病。铁稳态的改变被认为是由于PrPC通过其铁还原酶活性在神经元铁摄取中的功能受损所致。然而，缺乏明确的证据支持PrPC的铁还原酶活性。肾脏为这项评估提供了一个相关的模型，因为PrPC在肾脏中表达，与370In类似，肾脏近端小管细胞(PT)每天从肾小球滤液中重新吸收铁，需要铁还原酶活性。在此，我们报道PrPC在体内促进肾脏对转铁蛋白(Tf)和非IF结合铁(NTBI)的摄取，在体外主要促进PT细胞对转铁蛋白(Tf)和非IF结合铁(NTBI)的吸收。因此，PrP基因敲除(PrP-/-)肾脏通过灌胃、静脉或腹膜内给药对Fe-59的摄取显著低于PrP+/+对照组。用Fe-59选择性体内放射性标记血浆NTBI也有类似的结果。永生化PT细胞中外源性PrPC的表达定位于细胞膜和细胞内小泡，促进Fe-59-NTBI和Fe-59-Tf的跨上皮转运，少量增加Fe-59-Tf从顶端到基底外侧的转运。值得注意的是，PrP的铁还原酶缺陷突变体(PrP Delta(51-89))缺乏这种活性。此外，过量的NTBI和氯化血红素导致PrPC聚集成不溶于洗涤剂的形式，限制了铁的摄取。综上所述，这些观察表明PrPC通过其铁还原酶活性促进从肾小球滤液中回收铁，并调节肾脏铁代谢。
Brain iron-dyshomeostasis is an important cause of neurotoxicity in prion disorders, a group of neurodegenerative conditions associated with the conversion of prion protein (PrPC) from its normal conformation to an aggregated, PrP-scrapie (PrPSc) isoform. Alteration of iron homeostasis is believed to result from impaired function of PrPC in neuronal iron uptake via its ferrireductase activity. However, unequivocal evidence supporting the ferrireductase activity of PrPC is lacking. Kidney provides a relevant model for this evaluation because PrPC is expressed in the kidney, and similar to 370 in of iron are reabsorbed daily from the glomerular filtrate by kidney proximal tubule cells (PT), requiring ferrireductase activity. Here, we report that PrPC promotes the uptake of transferrin (Tf) and non-if-bound iron (NTBI) by the kidney in vivo and mainly NTBI by PT cells in vitro. Thus, uptake of Fe-59 administered by gastric gavage, intravenously, or intraperitoneally was significantly lower in PrP-knock-out (PrP-/-) kidney relative to PrP+/+ controls. Selective in vivo radiolabeling of plasma NTBI with Fe-59 revealed similar results. Expression of exogenous PrPC in immortalized PT cells showed localization on the plasma membrane and intracellular vesicles and increased transepithelial transport of Fe-59-NTBI and to a smaller extent Fe-59-Tf from the apical to the basolateral domain. Notably, the ferrireductase-deficient mutant of PrP (PrP Delta(51-89)) lacked this activity. Furthermore, excess NTBI and hemin caused aggregation of PrPC to a detergent-insoluble form, limiting iron uptake. Together, these observations suggest that PrPC promotes retrieval of iron from the glomerular filtrate via its ferrireductase activity and modulates kidney iron metabolism.