Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses
Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses
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DOI：
10.1074/jbc.m114.567685
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发表时间：
2014-09-26
影响因子：
4.8
通讯作者：
Dennery, Phyllis A.
中科院分区：
文献类型：
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作者：
Biswas, Chhanda;Shah, Nidhi;Dennery, Phyllis A.
在氧化损伤以及某些实体瘤和髓性白血病细胞中，血红素加氧酶-1（HO-1）（抗氧化、抗炎和抗凋亡的微粒体应激蛋白）以截短且无酶活性的形式迁移至细胞核。然而，HO-1在细胞核中的功能尚不完全清楚。核因子红细胞2相关因子2（Nrf 2），一种转录因子和许多抗氧化剂和抗凋亡蛋白（包括HO-1）的主要调节因子，也在氧化损伤和各种类型的癌症中积累在细胞核中。在这里，我们证明，在氧化应激，核HO-1与Nrf 2相互作用，并稳定它从糖原合成酶激酶3 β（GSK 3 β）介导的磷酸化加上泛素-蛋白酶体降解，从而延长其在细胞核中的积累。核HO-1对Nrf 2诱导后的这种调节对于II期解毒酶如NQO 1以及葡萄糖-6-磷酸脱氢酶（G6 PDH）（戊糖磷酸途径的调节剂）的优先转录是重要的。使用Nrf 2基因敲除细胞，我们进一步证明，核HO-1相关的细胞保护氧化应激依赖于HO-1/Nrf 2的相互作用。虽然众所周知，Nrf 2诱导HO-1导致减轻氧化应激，我们提出了一种新的机制，HO-1，通过调节Nrf 2的激活，设置一个适应性重编程，增强抗氧化防御。
With oxidative injury as well as in some solid tumors and myeloid leukemia cells, heme oxygenase-1 (HO-1), the anti-oxidant, anti-inflammatory, and anti-apoptotic microsomal stress protein, migrates to the nucleus in a truncated and enzymatically inactive form. However, the function of HO-1 in the nucleus is not completely clear. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor and master regulator of numerous antioxidants and anti-apoptotic proteins, including HO-1, also accumulates in the nucleus with oxidative injury and in various types of cancer. Here we demonstrate that in oxidative stress, nuclear HO-1 interacts with Nrf2 and stabilizes it from glycogen synthase kinase 3 beta (GSK3 beta)-mediated phosphorylation coupled with ubiquitin-proteasomal degradation, thereby prolonging its accumulation in the nucleus. This regulation of Nrf2 post-induction by nuclear HO-1 is important for the preferential transcription of phase II detoxification enzymes such as NQO1 as well as glucose-6-phosphate dehydrogenase (G6PDH), a regulator of the pentose phosphate pathway. Using Nrf2 knock-out cells, we further demonstrate that nuclear HO-1-associated cytoprotection against oxidative stress depends on an HO-1/Nrf2 interaction. Although it is well known that Nrf2 induces HO-1 leading to mitigation of oxidant stress, we propose a novel mechanism by which HO-1, by modulating the activation of Nrf2, sets an adaptive reprogramming that enhances antioxidant defenses.