HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells

Ghaziani, Tahereh; Shan, Ying; Lambrecht, Richard W.; Donohue, Susan E.; Pietschmann, Thomas; Bartenschlager, Ralf; Bonkovsky, Herbert L.

doi:10.1016/j.jhep.2005.12.020

Cited by 42 publications

(44 citation statements)

References 53 publications

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“…Recently we reported that the expression of hepatic HO-1 mRNA is increased in HCV replicon cells (56). In this study, we demonstrate that a chemically synthesized oligonucleotide, with sequence complementary to miR-122 (miR-122 antagomir), markedly inhibited HCV RNA replication in two Huh-7-derived HCV replicon cell lines.…”

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confidence: 64%

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

et al. 2007

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confidence: 64%

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

et al. 2007

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“…3) emphasizes that Bach1 repression reflects both Bach1 protein concentrations and other cellular factors such as heme. Down-regulation of Bach1 was also observed in cells expressing hepatitis C proteins (42).…”

Section: Discussionmentioning

confidence: 86%

Bach1 Repression of Ferritin and Thioredoxin Reductase1 Is Heme-sensitive in Cells and in Vitro and Coordinates Expression with Heme Oxygenase1, β-Globin, and NADP(H) Quinone (Oxido) Reductase1

Hintze¹,

Katoh

Igarashi

et al. 2007

Journal of Biological Chemistry

100

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Ferritin gene transcription is regulated by heme as is ferritin mRNA translation, which is mediated by the well studied mRNA⅐IRE/IRP protein complex. The heme-sensitive DNA sequence in ferritin genes is the maf recognition/antioxidant response element present in several other genes that are induced by heme and repressed by Bach1. We now report that chromatin immunoprecipitated with Bach1 antiserum contains ferritin DNA sequences. In addition, overexpression of Bach1 protein in the transfected cells decreased ferritin expression, indicating insufficient endogenous Bach1 for full repression; decreasing Bach1 with antisense RNA increased ferritin expression. Thioredoxin reductase1, a gene that also contains a maf recognition/ antioxidant response element but is less studied, responded similarly to ferritin, as did the positive controls heme oxygenase1 and NADP(H) quinone (oxido) reductase1. Bach1-DNA promoter interactions in cells were confirmed in vitro with soluble, recombinant Bach1 protein and revealed a quantitative range of Bach1/DNA stabilities: ferritin L ϳ ferritin H ϳ ␤-globin, ␤-globin ϳ 2-fold >heme oxygenase1 ‫؍‬ quinone reductase ␤-globin ϳ 4-fold >thioredoxin reductase1. Such results indicate the possibility that modulation of cellular Bach1 concentrations will have variable effects among the genes coordinately regulated by maf recognition/antioxidant response elements in iron/oxygen/antioxidant metabolism.Genes encoding proteins that manage proteins of iron and oxygen traffic and metabolism are at the nexus of chemical reactions that are both critical and dangerous to life. The iron porphyrin complex, heme, has emerged as a key signal for iron and oxygen metabolism genes, including ferritin L (ftl) 3 (1) and ferritin H (fth) (2). Transcriptional regulation of NADP(H) quinone (oxido) reductase (qr) (3), heme oxygenase1 (ho1) (4), and ␤-globin (5) by heme requires the maf recognition/antioxidant response element (MARE/ARE), a conserved regulatory sequence found in the promoter or enhancer, and the heme binding transcriptional repressor Bach1.Both ftl and fth contain heme-responsive canonical MARE/ ARE promoter sequences (1, 2). The role of Bach1 in hemeregulated ferritin transcription is not known. By contrast, the role of IRP1 and IRP2 in heme-regulated ftl and fth mRNA translation is known (6 -9). The translational mechanism uses IRP1 and IRP2 to coordinate fth and ftl mRNA regulation with that of several other mRNAs important in iron and oxygen homeostasis by binding to iron-responsive elements (IRE) in each of the mRNAs. The IRE is a specific three-dimensional loop-helix-loop-helix structure (10) in the noncoding regions of the mRNAs (11-16). Specific interactions between the iron regulatory proteins IRP1 and IRP2 and the different IREs in the mRNAs create a natural, combinatorial array of RNA⅐protein complexes (17). In the case of ferritin, when IRP1 or 2 are bound to the mRNA the ability of eukaryotic initiation factor 4F to recruit translational machinery to the mRNA is compromised and translat...

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“…An antiviral effect of HO-1 induction has been observed in infection studies of hepatitis C virus (HCV) (36), hepatitis B virus (HBV) (37), Ebola virus (38), enterovirus 71 (EV71) (39), vaccinia virus (40), and porcine reproductive and respiratory syndrome virus (41). Interestingly, HCV has been reported to downregulate HO-1 protein expression (42,43), although contrasting studies report HO-1 induction by HCV (44,45).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Gill

Kovacsics

Vance

et al. 2015

J Virol

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Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIVpositive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIVinfected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCEThe continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART. H eme oxygenase-1 (HO-1) is a highly inducible phase II d...

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HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells

Cited by 42 publications

References 53 publications

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

Reciprocal Effects of Micro-RNA-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

Bach1 Repression of Ferritin and Thioredoxin Reductase1 Is Heme-sensitive in Cells and in Vitro and Coordinates Expression with Heme Oxygenase1, β-Globin, and NADP(H) Quinone (Oxido) Reductase1

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

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