Heme acts through the Bach1b/Nrf2a-MafK pathway to regulate exocrine peptidase precursor genes in porphyric zebrafish.
Heme acts through the Bach1b/Nrf2a-MafK pathway to regulate exocrine peptidase precursor genes in porphyric zebrafish.
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血红素通过 Bach1b/Nrf2a-MafK 途径发挥作用，调节斑马鱼的外分泌肽酶前体基因。
DOI：
10.1242/dmm.014951
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发表时间：
2014-07
影响因子：
4.3
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhang S;Xu M;Huang J;Tang L;Zhang Y;Wu J;Lin S;Wang H
使用斑马鱼模型的肝红细胞生成性卟啉病（HEP），我们确定了一个以前未知的机制，血红素介导的外分泌酶原的调节。斑马鱼bach 1b、nrf 2a和mafK均在斑马鱼胰腺外分泌中表达。bach 1b的过表达或nrf 2a的敲低导致外分泌酶原表达的下调，而nrf 2a的过表达或bach 1b的敲低导致它们的上调。在体外荧光素酶测定表明，血红素激活的酶原在剂量依赖性的方式和酶原启动子的活动需要完整的Maf识别元件（MARE）基序。Bach 1b-MafK异二聚体抑制酶原启动子，而Nrf 2a-MafK异二聚体激活它们。此外，染色质免疫沉淀（ChIP）分析表明，MafK与酶原5′调控区的MARE位点结合。总而言之，这些数据表明，血红素刺激MafK占据的MARE位点上Bach 1b与Nrf 2a的交换，并且特别是在血红素缺乏的卟啉症中，抑制性Bach 1b-MafK异源二聚体占主导地位，在用氯高铁血红素处理后，它可以被交换为激活的Nrf 2a-MafK异源二聚体。这些结果提供了新的见解外分泌功能的调节，以及卟啉症的发病机制，并应有助于设计新的治疗这两种类型的疾病。
Using a zebrafish model of hepatoerythropoietic porphyria (HEP), we identify a previously unknown mechanism underlying heme-mediated regulation of exocrine zymogens. Zebrafish bach1b, nrf2a and mafK are all expressed in the zebrafish exocrine pancreas. Overexpression of bach1b or knockdown of nrf2a result in the downregulation of the expression of the exocrine zymogens, whereas overexpression of nrf2a or knockdown of bach1b cause their upregulation. In vitro luciferase assays demonstrate that heme activates the zymogens in a dosage-dependent manner and that the zymogen promoter activities require the integral Maf recognition element (MARE) motif. The Bach1b-MafK heterodimer represses the zymogen promoters, whereas the Nrf2a-MafK heterodimer activates them. Furthermore, chromatin immunoprecipitation (ChIP) assays show that MafK binds to the MARE sites in the 5′ regulatory regions of the zymogens. Taken together, these data indicate that heme stimulates the exchange of Bach1b for Nrf2a at MafK-occupied MARE sites and that, particularly in heme-deficient porphyria, the repressive Bach1b-MafK heterodimer dominates, which can be exchanged for the activating Nrf2a-MafK heterodimer upon treatment with hemin. These results provide novel insights into the regulation of exocrine function, as well as the pathogenesis of porphyria, and should be useful for designing new therapies for both types of disease.
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影响因子：
5.3
作者：
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