F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis.
F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis.
复制标题
DOI：
10.1074/jbc.m112.426171
复制
发表时间：
2013-01-04
期刊：
影响因子：
--
通讯作者：
Bruick RK
中科院分区：
文献类型：
--
作者：
Ruiz JC;Walker SD;Anderson SA;Eisenstein RS;Bruick RK
背景：FBXL 5是一种铁响应性E3泛素连接酶。结果如下：FBXL 5缺失小鼠在胚胎发生期间死亡，而Fbxl 5杂合子在喂食低铁饮食时由于铁吸收增强而表现得比野生型同窝出生的小鼠更好。结论：FBXL 5在体内维持细胞和全身铁稳态中起重要作用。FBXL 5是一种重要的生理铁传感器。细胞铁稳态的维持需要铁调节蛋白2（IRP 2）对铁代谢基因进行转录后调节。F-box和富含亮氨酸的重复蛋白5（FBXL 5）的hemerythrin样结构域是E3泛素连接酶亚基，可感知铁和氧的可用性，并促进铁充足细胞中的IRP 2降解。普遍表达的鼠Fbxl 5基因的破坏导致不能感知增加的细胞铁可用性，伴随着组成型IRP 2积累和IRP 2靶基因的错误表达。FBXL 5-null小鼠在胚胎发生过程中死亡，尽管通过同时删除IRP 2而不是IRP 1基因恢复了活力。含有单一功能性Fbxl 5等位基因的小鼠在喂食足够铁的饮食时表现得像它们的野生型同窝出生的小鼠。然而，与当喂食低铁饮食时表现出降低的血细胞比容和血红蛋白水平的野生型小鼠不同，Fbxl 5杂合子由于增加的铁吸收而保持正常的血液学值。IRP 2对低铁的反应性在杂合子的ESTA中特异性增强，并且伴随着二价金属转运蛋白-1的表达增加。这些结果证实了FBXL 5在体内维持细胞和全身铁稳态中的作用，并揭示了肠道凭借其独特的FBXL 5铁敏感性在其调节中的特殊作用。
Background: FBXL5 is an iron-responsive E3 ubiquitin ligase. Results: FBXL5-null mice die during embryogenesis, whereas Fbxl5 heterozygotes perform better than wild type littermates when fed a low iron diet due to enhanced iron absorption. Conclusion: FBXL5 plays an essential role in the in vivo maintenance of cellular and systemic iron homeostasis. Significance: FBXL5 is an essential physiological iron sensor. Maintenance of cellular iron homeostasis requires post-transcriptional regulation of iron metabolism genes by iron regulatory protein 2 (IRP2). The hemerythrin-like domain of F-box and leucine-rich repeat protein 5 (FBXL5), an E3 ubiquitin ligase subunit, senses iron and oxygen availability and facilitates IRP2 degradation in iron replete cells. Disruption of the ubiquitously expressed murine Fbxl5 gene results in a failure to sense increased cellular iron availability, accompanied by constitutive IRP2 accumulation and misexpression of IRP2 target genes. FBXL5-null mice die during embryogenesis, although viability is restored by simultaneous deletion of the IRP2, but not IRP1, gene. Mice containing a single functional Fbxl5 allele behave like their wild type littermates when fed an iron-sufficient diet. However, unlike wild type mice that manifest decreased hematocrit and hemoglobin levels when fed a low-iron diet, Fbxl5 heterozygotes maintain normal hematologic values due to increased iron absorption. The responsiveness of IRP2 to low iron is specifically enhanced in the duodena of the heterozygotes and is accompanied by increased expression of the divalent metal transporter-1. These results confirm the role of FBXL5 in the in vivo maintenance of cellular and systemic iron homeostasis and reveal a privileged role for the intestine in their regulation by virtue of its unique FBXL5 iron sensitivity.