Hypoxia post-translationally activates iron-regulatory protein 2
Hypoxia post-translationally activates iron-regulatory protein 2
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DOI：
10.1074/jbc.274.8.5047
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发表时间：
1999-02-19
影响因子：
4.8
通讯作者：
Leibold, EA
中科院分区：
文献类型：
--
作者：
Hanson, ES;Foot, LM;Leibold, EA
铁调节蛋白1和2 （IRP1和IRP2）是RNA结合蛋白，转录后调节mrna的表达，这些mrna编码参与维持铁和能量稳态的蛋白质。在这里，我们发现缺氧对人293和小鼠Hepa-1细胞中IRP1和IRP2的RNA结合活性有不同的调节，与IRP1相反，缺氧暴露会降低IRP1 RNA结合活性，而缺氧会增加IRP2 RNA结合活性。缺氧时IRP2 RNA结合活性的增加是由于IRP2蛋白水平的增加。钴通过激活缺氧诱导因子1 （HIF-1）模拟缺氧，也会增加IRP2蛋白水平；然而，钴诱导的IRP2缺乏RNA结合活性。在钴处理的提取物中加入还原剂可以恢复IRP2 RNA的结合活性。IRP2的缺氧激活不是因为HIF-1转录激活的增加，因为IRP2在缺乏功能性HIF-1 β亚基的Hepa-1细胞中积累，也不是因为IRP2 mRNA稳定性的增加。相反，我们的数据表明，缺氧通过涉及蛋白质稳定性的翻译后机制增加IRP2水平。缺氧时IRP1和IRP2的差异调控可能调控了缺氧适应所需的特定IRP靶mrna的表达。此外，这些数据暗示缺氧诱导的IRP2转录后调控和HIF-1 α之间的机制相似。
Iron-regulatory proteins 1 and 2 (IRP1 and IRP2) are RNA-binding proteins that post-transcriptionally regulate the expression of mRNAs that code for proteins involved in the maintenance of iron and energy homeostasis, Here we show that hypoxia differentially regulates the RNA binding activities of IRP1 and IRP2 in human 293 and in mouse Hepa-1 cells, In contrast to IRP1, where hypoxic exposure decreases IRP1 RNA binding activity, hypoxia increases IRP2 RNA binding activity. The hypoxic increase in IRP2 RNA binding activity results from increased IRP2 protein levels. Cobalt, which mimics hypoxia by activation of hypoxia-inducible factor 1 (HIF-1), also increases IRP2 protein levels; however, cobalt-induced IRP2 lacks RNA binding activity. Addition of a reductant to cobalt-treated extracts restored IRP2 RNA binding activity. Hypoxic activation of IRP2 is not because of an increase in transcriptional activation by HIF-1, because IRP2 accumulates in Hepa-1 cells lacking a functional HIF-1 beta subunit, nor is it because of an increase in IRP2 mRNA stability. Rather, our data indicate that hypoxia increases IRP2 levels by a post-translational mechanism involving pro tein stability. Differential regulation of IRP1 and IRP2 during hypoxia may regulate specific IRP target mRNAs whose expression is required for hypoxic adaptation. Furthermore, these data imply mechanistic parallels between the hypoxia-induced post-transcriptional regulation of IRP2 and HIF-1 alpha.