Nuclear Heme Oxygenase-1 (HO-1) Modulates Subcellular Distribution and Activation of Nrf2, Impacting Metabolic and Anti-oxidant Defenses

• Published in: The Journal of biological chemistry 2014-09, Vol.289 (39), p.26882-26894
• Main Authors: Biswas, Chhanda, Shah, Nidhi, Muthu, Manasa, La, Ping, Fernando, Amal P., Sengupta, Shaon, Yang, Guang, Dennery, Phyllis A.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - metabolism; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cells, Cultured; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase - metabolism; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress; Phosphorylation - genetics; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proteolysis; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.567685

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 3β (GSK3β)-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.