Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition
Secreted glyceraldehye-3-phosphate dehydrogenase is a multifunctional autocrine transferrin receptor for cellular iron acquisition
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DOI：
10.1016/j.bbagen.2013.03.019
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发表时间：
2013-06-01
影响因子：
3
通讯作者：
Raje, Manoj
中科院分区：
文献类型：
--
作者：
Sheokand, Navdeep;Kumar, Santosh;Raje, Manoj
背景：长期以来，人们认为哺乳动物细胞利用专门的膜锚定受体获得转铁蛋白（Tf）结合铁。在这里，我们报告说，在增加铁的需求，细胞分泌的糖酵解酶甘油醛-3-磷酸脱氢酶（GAPDH），提高细胞的Tf和铁的摄取。方法：这些观察可以通过利用纯化GAPDH注射到小鼠以及补充时，在培养基中的模型细胞系和主要细胞类型，在铁代谢中发挥关键作用，模仿。转铁蛋白和铁传递进行了评估，通过生物化学，生物物理和成像为基础的assays.Results：这种模式的铁摄取是一个饱和的，能量依赖性的途径，利用筏以及非筏域的细胞膜，也涉及膜蛋白CD 87（uPAR）。Tf内化通过这种模式也catabolized.Conclusions：我们的研究表明，即使在细胞类型，表达已知的表面受体为基础的机制转铁蛋白摄取，更多的转铁蛋白是通过这条路线，这代表了一个隐藏的维度铁homeostasis.General Significance：铁是一个必不可少的微量金属几乎所有的生物体，但它的收购提出了重大挑战。目前的范式是，生物体已经发展出精心策划和进化的机制，涉及铁载体分子及其特异性受体，以调节其吸收，运输，储存和动员。我们的研究揭示了大量铁运输的隐藏和原始途径，涉及一种分泌型受体，该受体是一种多功能糖酵解酶，在感染性疾病和癌症等病理条件下具有影响。(C)2013爱思唯尔有限公司版权所有。
Background: The long held view is that mammalian cells obtain transferrin (Tf) bound iron utilizing specialized membrane anchored receptors. Here we report that, during increased iron demand, cells secrete the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) which enhances cellular uptake of Tf and iron.Methods: These observations could be mimicked by utilizing purified GAPDH injected into mice as well as when supplemented in culture medium of model cell lines and primary cell types that play a key role in iron metabolism. Transferrin and iron delivery was evaluated by biochemical, biophysical and imaging based assays.Results: This mode of iron uptake is a saturable, energy dependent pathway, utilizing raft as well as non-raft domains of the cell membrane and also involves the membrane protein CD87 (uPAR). Tf internalized by this mode is also catabolized.Conclusions: Our research demonstrates that, even in cell types that express the known surface receptor based mechanism for transferrin uptake, more transferrin is delivered by this route which represents a hidden dimension of iron homeostasis.General significance: Iron is an essential trace metal for practically all living organisms however its acquisition presents major challenges. The current paradigm is that living organisms have developed well orchestrated and evolved mechanisms involving iron carrier molecules and their specific receptors to regulate its absorption, transport, storage and mobilization. Our research uncovers a hidden and primitive pathway of bulk iron trafficking involving a secreted receptor that is a multifunctional glycolytic enzyme that has implications in pathological conditions such as infectious diseases and cancer. (C) 2013 Elsevier B.V. All rights reserved.