Natural resistance–associated macrophage protein 1 (Nramp1) was originally discovered as a genetic determinant of resistance against multiple intracellular pathogens, including Leishmania. It encodes a transmembrane protein of the phago‐endosomal compartments, where it functions as an iron transporter. But the mechanism by which Nramp1 controls host–pathogen dynamics and determines final outcome of an infection is yet to be fully deciphered. Whether the expression of Nramp1 is altered in response to a pathogen attack is also unknown. To address these, Nramp1 status was examined in Leishmania major–infected murine macrophages. We observed that at 12 hrs post infection, there was drastic lowering of Nramp1 level accompanied by increased phagolysosomal iron content and enhanced intracellular parasite growth. Leishmania infection–induced Nramp1 downregulation was caused by ubiquitin‐proteasome degradation pathway, which in turn was found to be mediated by the iron‐regulatory peptide hormone hepcidin. Blocking of Nramp1 degradation with proteasome inhibitor or transcriptional agonist of hepcidin resulted in depletion of phagolysosomal iron pool that led to significant reduction of intracellular parasite burden. Interestingly, Nramp1 level was restored to normalcy after 30 hrs of infection with a concomitant drop in phagolysosomal iron, which is suggestive of a host counteractive response to deprive the pathogen of this essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the host–pathogen battle for phagolysosomal iron. We also report Nramp1 as a novel target for hepcidin, and this ‘hepcidin‐Nramp1’ axis may have a broader role in regulating macrophage iron homeostasis.

中文翻译：

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利什曼原虫感染触发铁调素介导的 Nramp1 蛋白酶体降解，以增加吞噬溶酶体铁的可用性。

自然抗性相关巨噬细胞蛋白 1 (Nramp1) 最初被发现是对多种细胞内病原体（包括利什曼原虫）抗性的遗传决定因素。它编码吞噬-内体区室的跨膜蛋白，在其中起到铁转运蛋白的作用。但是 Nramp1 控制宿主-病原体动力学并决定感染最终结果的机制尚未完全破译。Nramp1 的表达是否因病原体攻击而发生改变也是未知的。为了解决这些问题，在主要利什曼原虫中检查了 Nramp1 状态– 感染的鼠巨噬细胞。我们观察到在感染后 12 小时，Nramp1 水平急剧降低，伴随着吞噬溶酶体铁含量的增加和细胞内寄生虫生长的增强。利什曼原虫感染诱导的 Nramp1 下调是由泛素-蛋白酶体降解途径引起的，而该途径又被发现是由铁调节肽激素铁调素介导的。用蛋白酶体抑制剂或铁调素转录激动剂阻断 Nramp1 降解导致吞噬溶酶体铁池耗尽，从而导致细胞内寄生虫负担显着减少。有趣的是，Nramp1 水平在感染 30 小时后恢复正常，同时吞噬溶酶体铁含量下降，这表明宿主的反作用反应剥夺了病原体的这种必需微量营养素。综上所述，我们的研究表明 Nramp1 是宿主 - 病原体争夺吞噬溶酶体铁的核心参与者。我们还将 Nramp1 报告为铁调素的新靶点，