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PubMed: 25301065

Title
Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress.
Journal
Cell death and differentiation
Volume
22
Issue
None
Pages
597-611
Date
2015-04-01
Authors
Deuel JW | Schaer DJ | Buehler PW | Opitz L | Schaer CA | Spahn DR | Vallelian F | Engelsberger W | Karnaukhova E | Lönn M | Puglia M | Schauer S | Stocker R

Evidence c6ccc4b26a
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Identical results were obtained with the antioxidant dithiothreitol (DTT) (data not shown).

a(CHEBI:"D-1,4-dithiothreitol") decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Evidence b742968378
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In contrast, at an equal antioxidant concentration, Trolox completely blocked heme-triggered lipid peroxidation (measured as production of thiobarbituric acid reactive substances (TBARS)) in soybean lecithin micelles (Figure 7g).

a(CHEBI:Trolox) decreases bp(MESH:"Lipid Peroxidation") View Subject | View Object

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a(CHEBI:heme) increases bp(MESH:"Lipid Peroxidation") View Subject | View Object

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Evidence e37054cf4a
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The Hmox1 (− /− ) MEF cells expressed no functional Hmox1 mRNA (Figure 1a) and as a result accumulated more cell-associated heme during extracellular exposure compared with wild-type cells (Figure 1b).

a(CHEBI:heme) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence d04659f0aa
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During heme exposure the Hmox1 (−/ −) cells show a dose-dependent decrease in mitochondrial function as indicated by decreased cellular ATP (Figure 1c) and parallel induction of caspase 3/7 activity (Figure 1d) as well as nuclear condensation (Figure 1e) that occurred at heme concentrations exceeding 10 μM.

a(CHEBI:heme) positiveCorrelation path(MESH:"Mitochondrial Diseases") View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation path(MESH:"Mitochondrial Diseases") View Subject | View Object

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path(MESH:"Mitochondrial Diseases") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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path(MESH:"Mitochondrial Diseases") negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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Evidence 2a7030cd95
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Beyond this common protein expression signature, the toxic heme response of Hmox1 (− /−) MEF cells was uniquely characterized by a cluster of strongly upregulated proteins. Within this cluster we identified ubiquitin, the ubiquitin adaptor protein sequestosome/p-62 (Sqstm1), a number of heat shock proteins, as well as antioxidant defense proteins (i.e., peroxiredoxins, glutathione-S-transferase, and thioredoxin reductase).

a(CHEBI:heme) increases p(PFAM:ubiquitin) View Subject | View Object

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a(CHEBI:heme) increases p(MGI:Sqstm1) View Subject | View Object

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a(CHEBI:heme) increases complex(p(MGI:Prdx1), p(MGI:Prdx2), p(MGI:Prdx3), p(MGI:Prdx4), p(MGI:Prdx5), p(MGI:Prdx6)) View Subject | View Object

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a(CHEBI:heme) increases p(INTERPRO:"Glutathione Transferase family") View Subject | View Object

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a(CHEBI:heme) increases p(INTERPRO:"Thioredoxin reductase") View Subject | View Object

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Evidence 5a0820e873
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We confirmed by selected reaction monitoring (SRM) mode mass spectrometry (Figure 3a) and western blot (Figures 3c and d), respectively, that heme increased Sqstm1, ubiquitin, and Hsp70, with a much stronger response in Hmox1 (−/− ) compared with Hmox1 (+/+) MEF cells.

a(CHEBI:heme) increases p(PFAM:ubiquitin) View Subject | View Object

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a(CHEBI:heme) increases p(MGI:Sqstm1) View Subject | View Object

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a(CHEBI:heme) increases p(MGI:Hspa2) View Subject | View Object

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p(MGI:Hmox1) decreases p(MGI:Sqstm1) View Subject | View Object

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p(MGI:Hmox1) decreases p(PFAM:ubiquitin) View Subject | View Object

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p(MGI:Hmox1) decreases p(MGI:Hspa2) View Subject | View Object

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Evidence a470d364fc
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At higher extracellular heme concentrations, heme exposure dose dependently caused accumulation of myc-tagged Sqstm1 (Figure 3g).

a(CHEBI:heme) increases p(MGI:Sqstm1) View Subject | View Object

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Evidence 317972b117
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This result strongly supports that high cellular heme concentration impairs degradation of Sqstm1 by the homeostatic protein degradation pathways.

a(CHEBI:heme) negativeCorrelation deg(p(MGI:Sqstm1)) View Subject | View Object

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deg(p(MGI:Sqstm1)) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence 6a66e6803b
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We also confirmed ferritin light chain enhancement as a common response to heme exposure of Hmox1 (+/+) and Hmox1 (−/ −) MEF cells (Figure 3a).

a(CHEBI:heme) increases p(MGI:Ftl1) View Subject | View Object

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Evidence fbecad7bbc
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These data, in addition to older biochemical studies that empirically used heme to inhibit proteasome function in biochemical assays, led us to the hypothesis that excessive intracellular heme could disrupt cellular protein homeostasis by an inhibitory action on the proteasome.

a(CHEBI:heme) negativeCorrelation bp(GO:"cellular homeostasis") View Subject | View Object

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bp(GO:"cellular homeostasis") negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence d0779c1f72
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The proteasome is the principal pathway to remove senescent and damaged proteins, and intact proteasome function is essential to preserve and repair cellular homeostasis during oxidative stress, such as that triggered by heme exposure.27

a(CHEBI:heme) negativeCorrelation bp(GO:"cellular homeostasis") View Subject | View Object

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bp(GO:"cellular homeostasis") negativeCorrelation a(CHEBI:heme) View Subject | View Object

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bp(GO:"cellular homeostasis") positiveCorrelation act(p(PFAM:Proteasome)) View Subject | View Object

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act(p(PFAM:Proteasome)) positiveCorrelation bp(GO:"cellular homeostasis") View Subject | View Object

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Evidence 7b67974f0a
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Interestingly, besides the common cluster of upregulated proteins, which includes Sqstm1, ubiquitin, and a number of heat shock and oxidative defence proteins, we also observed that heme strongly suppressed the abundance of collagen (Col1a1) 1 protein.

a(CHEBI:heme) decreases p(MGI:Col1a1) View Subject | View Object

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Evidence 86cd7be18b
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Collectively, these data support that heme is an inhibitor of proteasome activity in different cell types and in a cell-free system.

a(CHEBI:heme) decreases act(p(PFAM:Proteasome)) View Subject | View Object

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Evidence efe4e2db44
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In addition to this well-established role of heme as an oxidant, a novel and consistent finding of the present study is that excessive heme levels lead to dysfunctional cellular protein degradation by the proteasome.

a(CHEBI:heme) decreases act(p(PFAM:Proteasome)) View Subject | View Object

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Evidence 1f3c3069c7
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Accordingly, higher levels of lipid peroxide-protein adducts were detected in heme-treated Hmox1 (− /−) than in Hmox1 (+/+) MEF cells when the cells were heme exposed in the presence of an alkyne-tagged analog of linoleic acid, which is an unsaturated, heme-reactive fatty acid (Supplementary Figure 3).

a(CHEBI:heme) positiveCorrelation a(MESH:"Lipid Peroxides") View Subject | View Object

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a(MESH:"Lipid Peroxides") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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a(MESH:"Lipid Peroxides") negativeCorrelation p(MGI:Hmox1) View Subject | View Object

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p(MGI:Hmox1) negativeCorrelation a(MESH:"Lipid Peroxides") View Subject | View Object

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Evidence b18aa92997
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Proteasome inhibition promotes accumulation of damaged proteins and may thereby critically enhance the cellular injury that is triggered by oxidative heme effects.

a(MESH:"Proteasome Inhibitors") positiveCorrelation bp(GO:"cellular response to oxidative stress") View Subject | View Object

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bp(GO:"cellular response to oxidative stress") positiveCorrelation a(MESH:"Proteasome Inhibitors") View Subject | View Object

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