Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes
Iron chelators modulate the fusogenic properties of Salmonella-containing phagosomes
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DOI：
10.1073/pnas.0937287100
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发表时间：
2003-05-13
影响因子：
11.1
通讯作者：
Gros, P
中科院分区：
文献类型：
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作者：
Jabado, N;Cuellar-Mata, P;Gros, P
在巨噬细胞中，二价阳离子转运蛋白Nramp 1从溶酶体区室募集到这些细胞中形成的吞噬体的膜。Nramp 1突变导致对细胞内病原体如沙门氏菌和分枝杆菌感染的易感性。沙门氏菌的细胞内存活涉及在内膜隔室（含沙门氏菌的空泡，SCV）中的分离，该隔室对甘露糖-6-磷酸受体（M6 PR）保持阴性，并且不能进入内吞途径。Nramp 1在SCVs膜上的表达刺激M6 PR的获得和对新形成的内体的可接近性。Nramp 1介导的铁运输对SCV成熟的可能作用进行了研究与膜渗透铁螯合剂。用去铁胺或水杨醛异可丁酰腙预处理Nramp 1突变小鼠或RAW264.7巨噬细胞（来自携带Nramp 1（D169）缺陷等位基因的BALB/c小鼠）的原代巨噬细胞，恢复了M6 PR的募集，并将液相标记物罗丹明葡聚糖递送至SCV，其水平与表达WT Nramp 1的巨噬细胞中观察到的水平相似。这种效应是特定的和剂量依赖性的，可以通过与过量的铁预孵育而消除。这些数据表明，Nramp 1介导的巨噬细胞中铁和可能其他二价金属的剥夺拮抗了沙门氏菌改变吞噬体成熟的能力。
In macrophages, the divalent cations transporter Nramp1 is recruited from the lysosomal compartment to the membrane of phagosomes formed in these cells. Nramp1 mutations cause susceptibility to infection with intracellular pathogens such as Salmonella and Mycobacterium. Intracellular survival of Salmonella involves segregation in an endomembrane compartment (Salmonella-containing vacuole, SCV) that remains negative for the mannose-6-phosphate receptor (M6PR) and that is inaccessible to the endocytic pathway. Expression of Nramp1 at the membrane of SCVs stimulates both acquisition of M6PR and accessibility to newly formed endosomes. The possible role of Nramp1-mediated iron transport on SCV maturation was investigated with membrane-permeant iron chelators. Pretreatment of primary macrophages from Nramp1 mutant mice or of RAW264.7 macrophages (from BALB/c mice bearing an Nramp1(D169)-deficient allele) with either desferrioxamine or salicylaldehyde isocotinoyl hydrazone restored recruitment of M6PR and delivery of the fluid phase marker rhodamine dextran to SCVs to levels similar to those seen in macrophages expressing WT Nramp1. The effect was specific and dose-dependent and could be abrogated by preincubation with excess iron. These data suggest that Nramp1-mediated deprivation of iron and possibly of other divalent metals in macrophages antagonizes the ability of Salmonella to alter phagosome maturation.