ER stress controls iron metabolism through induction of hepcidin.
ER stress controls iron metabolism through induction of hepcidin.
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DOI：
10.1126/science.1176639
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发表时间：
2009-08-14
期刊：
影响因子：
--
通讯作者：
Pietrangelo A
中科院分区：
文献类型：
--
作者：
Vecchi C;Montosi G;Zhang K;Lamberti I;Duncan SA;Kaufman RJ;Pietrangelo A
肝磷脂是一种肽激素，由肝脏分泌，控制体内铁稳态。Hepcidin的过量产生导致炎症性贫血，而其缺乏导致血色素沉着症。炎症和铁是已知的hepcidin表达的细胞外刺激。我们发现内质网（ER）应激也诱导hepcidin表达并引起小鼠低铁血症和脾铁隔离。CREBH（环AMP反应元件结合蛋白H）是内质网应激激活的转录因子，与hepcidin启动子结合并转激活。在CREBH敲除小鼠中，外源性毒素或内质网未折叠蛋白积累对Hepcidin的诱导是有缺陷的，这表明CREBH在内质网应激调节的Hepcidin表达中起作用。内质网应激对hepcidin的调节将参与蛋白质质量控制的细胞内反应与先天免疫和铁稳态联系起来。
Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element–binding protein H), an ER stress–activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress–regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.
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