Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins
Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins
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DOI：
10.1038/nature06934
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发表时间：
2008-06-19
期刊：
影响因子：
64.8
通讯作者：
Hamza, Iqbal
中科院分区：
文献类型：
--
作者：
Rajagopal, Abbhirami;Rao, Anita U.;Hamza, Iqbal
血红蛋白是金属卟啉，可作为各种生物过程的辅基，包括呼吸、气体传感、异生物质解毒、细胞分化、生物钟控制、代谢重编程和 microRNA 处理(1-4)。除少数例外，血红素是通过多步生物合成途径合成的，该途径包含在整个进化过程中高度保守的特定中间体(5)。尽管我们对血红素生物合成和降解有广泛的了解，但介导细胞内血红素运输的细胞途径和分子尚不清楚。鉴定血红素运输途径的实验挫折是无法将高度调节的细胞合成和血红素降解与细胞内运输事件分开(6)。秀丽隐杆线虫和相关蠕虫是天然的血红素营养缺陷型动物，它们获得环境血红素以掺入具有脊椎动物直向同源物的血红素蛋白中(7)。在这里，我们通过利用这种营养缺陷来鉴定秀丽隐杆线虫中的 HRG-1 蛋白，表明这些蛋白对于蠕虫和脊椎动物的血红稳态和正常发育至关重要。线虫中 HRG-1 或其旁系同源物 HRG-4 的耗竭会导致生物体血红素感应破坏以及对血红素类似物的异常反应。 HRG-1 和 HRG-4 是以前未知的跨膜蛋白，它们驻留在不同的细胞内区室中。斑马鱼中 HRG-1 的短暂敲低会导致脑积水、卵黄管畸形，最引人注目的是，会导致红细胞生成表型的严重缺陷，但线虫 HRG-1 可以完全挽救这些缺陷。人类和蠕虫蛋白定位在一起，结合并运输血红素，从而建立了 HRG-1 的进化保守功能。这些发现揭示了动物细胞血红素运输的保守途径，定义了真核血红素运输的模型。因此，揭示线虫中血红素运输的机制可能有助于了解人类血红素代谢紊乱，并揭示开发抗蠕虫药以对抗蠕虫感染的新药物靶点。
Haems are metalloporphyrins that serve as prosthetic groups for various biological processes including respiration, gas sensing, xenobiotic detoxification, cell differentiation, circadian clock control, metabolic reprogramming and microRNA processing(1-4). With a few exceptions, haem is synthesized by a multistep biosynthetic pathway comprising defined intermediates that are highly conserved throughout evolution(5). Despite our extensive knowledge of haem biosynthesis and degradation, the cellular pathways and molecules that mediate intracellular haem trafficking are unknown. The experimental setback in identifying haem trafficking pathways has been the inability to dissociate the highly regulated cellular synthesis and degradation of haem from intracellular trafficking events(6). Caenorhabditis elegans and related helminths are natural haem auxotrophs that acquire environmental haem for incorporation into haemoproteins, which have vertebrate orthologues(7). Here we show, by exploiting this auxotrophy to identify HRG-1 proteins in C. elegans, that these proteins are essential for haem homeostasis and normal development in worms and vertebrates. Depletion of hrg-1, or its paralogue hrg-4, in worms results in the disruption of organismal haem sensing and an abnormal response to haem analogues. HRG-1 and HRG-4 are previously unknown transmembrane proteins, which reside in distinct intracellular compartments. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations and, most strikingly, profound defects in erythropoiesis-phenotypes that are fully rescued by worm HRG-1. Human and worm proteins localize together, and bind and transport haem, thus establishing an evolutionarily conserved function for HRG-1. These findings reveal conserved pathways for cellular haem trafficking in animals that define the model for eukaryotic haem transport. Thus, uncovering the mechanisms of haem transport in C. elegans may provide insights into human disorders of haem metabolism and reveal new drug targets for developing anthelminthics to combat worm infestations.