Heme induces ubiquitination and degradation of the transcription factor bach1
Heme induces ubiquitination and degradation of the transcription factor bach1
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DOI：
10.1128/mcb.02415-06
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发表时间：
2007-10-01
影响因子：
5.3
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Zenke-Kawasaki, Yukari;Dohi, Yoshihiro;Igarashi, Kazuhiko
转录抑制因子Bach1是血红素的感受器和效应器，调节血红素加氧酶I和珠蛋白基因的表达。血红素与Bach1结合，抑制其DNA结合活性，并诱导其核输出。我们发现，在NIH3T3细胞、小鼠胚胎成纤维细胞和小鼠红白血病细胞中，氯化血红素进一步诱导内源性Bach1的降解。相比之下，血红素合成的抑制剂琥珀酰丙酮导致小鼠胚胎成纤维细胞中Bach1的积累，表明生理水平的血红素调节Bach1的周转。氯化高铁血红素诱导Bach1的泛素化和过表达的Bach1迅速降解。HOIL-1是一种识别血红素结合的氧化铁调节蛋白2的泛素蛋白连接酶，当两者在NIH 3T3细胞中过表达时，HOIL-1被发现与Bach1结合。HOIL-1在体外纯化的泛素化系统中刺激Bach1的多泛素化，依赖于Bach1完整的血红素结合基序。在小鼠红白血病细胞中表达显性负性HOIL-1导致内源性Bach1具有更高的稳定性，增加了血红素调节的降解涉及HOIL-1在小鼠红白血病细胞中的可能性。这些结果表明，细胞内的血红素调节Bach1的多泛素化和降解。
The transcription repressor Bach1 is a sensor and effector of heme that regulates the expression of heme oxygenase I and globin genes. Heme binds to Bach1, inhibiting its DNA binding activity and inducing its nuclear export. We found that hemin further induced the degradation of endogenous Bach1 in NIH 3T3 cells, murine embryonic fibroblasts, and murine erythroleukemia cells. In contrast, succinylacetone, an inhibitor of heme synthesis, caused accumulation of Bach1 in murine embryonic fibroblasts, indicating that physiological levels of heme regulated the Bach1 turnover. Polyubiquitination and rapid degradation of overexpressed Bach1 were induced by hemin treatment. HOIL-1, an ubiquitin-protein ligase which recognizes heme-bound, oxidized iron regulatory protein 2, was found to bind with Bach1 when both were overexpressed in NIH 3T3 cells. HOIL-1 stimulated the polyubiquitination of Bach1 in a purified in vitro ubiquitination system depending on the intact heme binding motifs of Bach1. Expression of dominant-negative HOIL-1 in murine erythroleukemia cells resulted in higher stability of endogenous Bach1, raising the possibility that the heme-regulated degradation involved HOIL-1 in murine erythroleukemia cells. These results suggest that heme within a cell regulates the polyubiquitination and degradation of Bach1.