Prion protein functions as a ferrireductase partner for ZIP14 and DMT1.
Prion protein functions as a ferrireductase partner for ZIP14 and DMT1.
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DOI：
10.1016/j.freeradbiomed.2015.03.037
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发表时间：
2015-07
影响因子：
7.4
通讯作者：
Singh, Neena
中科院分区：
文献类型：
--
作者：
Tripathi, Ajai K.;Haldar, Swati;Qian, Juan;Beserra, Amber;Suda, Srinivas;Singh, Ajay;Hopfer, Ulrich;Chen, Shu G.;Garrick, Michael D.;Turner, Jerrold R.;Knutson, Mitchell D.;Singh, Neena
过量的循环铁储存在肝脏中，需要通过铁还原酶(FR)蛋白在质膜和内体分别还原非转铁蛋白结合铁(NTBI)和转铁蛋白(Tf)铁，通过二价金属转运蛋白进行生物膜的运输。在这里，我们报道了PrPC，一种在神经细胞中普遍表达的糖蛋白，作为二价金属转运蛋白1(DMT1)和ZIP14的受体伙伴。因此，PrP基因敲除(PrP−/−)小鼠缺乏PrPC会导致肝脏铁储存显著减少，这一缺陷不能通过口服或腹膜内途径长期或急性给铁来纠正。同样，优先用~(59)Fe标记循环中的NTBI显示，与匹配的PrP+/+对照相比，PrP−/−小鼠肝脏对NTBI的摄取和储存显著减少。然而，在PrP−/−小鼠中，铁蛋白结合铁的摄取、储存和利用不需要减少摄取，这表明了对缺铁的代偿反应。外源PrPC在HepG2-细胞中的表达增加了对培养液中铁(Fe3+)的摄取和储存，而不是Fe2+，从而支持PrPC作为质膜FR的功能。PrPC与ZIP14和DMT1在HepG2细胞中的共表达显著增加了Fe3+的摄取，令人惊讶的是，与全长PrPC相比，缺少FR结构域的N端截短PrPC形式的比例增加。总之，这些观察表明PrPC通过其FR活性促进并可能调节NTBI通过DMT1和Zip14的摄取。这些观察结果对生理和病理条件下神经元铁稳态的影响进行了讨论。
Excess circulating iron is stored in the liver, and requires reduction of non-Tf-bound-iron (NTBI) and transferrin (Tf)-iron at the plasma membrane and endosomes respectively by ferrireductase (FR) proteins for transport across biological membranes through divalent metal transporters. Here, we report that prion-protein (PrPC), a ubiquitously expressed glycoprotein most abundant on neuronal cells, functions as a FR partner for divalent-metal transporter-1 (DMT1) and ZIP14. Thus, absence of PrPC in PrP-knock-out (PrP−/−) mice resulted in markedly reduced liver iron stores, a deficiency that was not corrected by chronic or acute administration of iron by the oral or intra-peritoneal routes. Likewise, preferential radiolabeling of circulating NTBI with 59Fe revealed significantly reduced uptake and storage of NTBI by the liver of PrP−/− mice relative to matched PrP+/+ controls. However, uptake, storage, and utilization of ferritin-bound iron that does not require reduction for uptake was increased in PrP−/− mice, indicating a compensatory response to the iron-deficiency. Expression of exogenous PrPC in HepG2-cells increased uptake and storage of ferric-iron (Fe3+), not ferrous-iron (Fe2+) from the medium, supporting the function of PrPC as a plasma membrane FR. Co-expression of PrPC with ZIP14 and DMT1 in HepG2 cells increased uptake of Fe3+ significantly, and surprisingly, increased the ratio of N-terminally truncated PrPC forms lacking the FR domain relative to full-length PrPC. Together, these observations indicate that PrPC promotes, and possibly regulates the uptake of NTBI through DMT1 and Zip14 via its FR activity. Implications of these observations for neuronal iron homeostasis under physiological and pathological conditions are discussed.
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影响因子：
5.6
作者：
Ehsani, Sepehr;Salehzadeh, Ashkan;Schmitt-Ulms, Gerold
通讯作者：
Schmitt-Ulms, Gerold
影响因子：
3.2
作者：
MCMILLAN, PN;HIXSON, DC;JAUREGUI, HO
通讯作者：
JAUREGUI, HO
影响因子：
4.2
作者：
Kaur, Deepinder;Peng, Jun;Andersen, Julie K.
通讯作者：
Andersen, Julie K.
影响因子：
3.4
作者：
Martin, Dustin P.;Anantharam, Vellareddy;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
影响因子：
4.8
作者：
Haldar, Swati;Tripathi, Ajai;Singh, Neena
通讯作者：
Singh, Neena