Hemozoin produced by mammals confers heme tolerance
Hemozoin produced by mammals confers heme tolerance
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DOI：
10.7554/elife.49503
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发表时间：
2019-10-01
期刊：
影响因子：
7.7
通讯作者：
Hamza, Iqbal
中科院分区：
文献类型：
--
作者：
Pek, Rini H.;Yuan, Xiaojing;Hamza, Iqbal
游离血红素具有细胞毒性，如溶血性疾病和血红素再循环和解毒途径中的遗传缺陷所例示。因此，迄今为止，在哺乳动物细胞中尚未观察到血红素的细胞内积累。在这里，我们表明，小鼠缺乏血红素转运蛋白SLC48A1（也称为HRG1）积累超过10倍过量血红素网状内皮巨噬细胞溶酶体是10至100倍比正常。巨噬细胞通过将这些高浓度的血红素结晶成疟原虫色素来耐受这些高浓度的血红素，而疟原虫色素迄今仅在吸血生物中发现。SLC48A1缺乏导致红细胞成熟受损，并且不能对缺铁做出系统性反应。完全的血红素耐受需要完全可操作的血红素降解途径，因为HMOX1的单倍不足与SLC 48 A1失活结合导致围产期致死，证明血红素转运和降解之间的合成致死相互作用。我们的研究建立了哺乳动物形成疟原虫色素作为一个以前未被怀疑的血红素耐受途径。
Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by crystallizing them into hemozoin, which heretofore has only been found in blood-feeding organisms. SLC48A1 deficiency results in impaired erythroid maturation and an inability to systemically respond to iron deficiency. Complete heme tolerance requires a fully-operational heme degradation pathway as haplo insufficiency of HMOX1 combined with SLC48A1 inactivation causes perinatal lethality demonstrating synthetic lethal interactions between heme transport and degradation. Our studies establish the formation of hemozoin by mammals as a previously unsuspected heme tolerance pathway.