title: Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2, impacting metabolic and anti-oxidant defenses.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Pennsylvania Philadelphia, Pennsylvania 19104 and; Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Chhanda
authors.initials: C
authors.lastname: Biswas
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Shah
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Manasa
authors.initials: M
authors.lastname: Muthu
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Ping
authors.initials: P
authors.lastname: La
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Amal P
authors.initials: AP
authors.lastname: Fernando
authors.affiliation: Department of Pediatrics, University of Pennsylvania Philadelphia, Pennsylvania 19104 and; Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Shaon
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, University of Pennsylvania Philadelphia, Pennsylvania 19104 and; Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104. Electronic address: dennery@email.chop.edu.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Dennery
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis
chemical_list: D000975:Antioxidants; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D005954:Glucosephosphate Dehydrogenase; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: Heme Oxygenase; Nuclear Factor 2 (Erythroid-derived 2-like Factor) (NFE2L2) (Nrf2); Nuclear Translocation; Oxidative Stress; Protein-Protein Interaction
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