Degradation of heme oxygenase‐1 by the immunoproteasome in astrocytes: A potential interferon‐γ‐dependent mechanism contributing to HIV neuropathogenesis

• Published in: Glia Vol. 65; no. 8; pp. 1264 - 1277
• Main Authors: Kovacsics, Colleen E., Gill, Alexander J., Ambegaokar, Surendra S., Gelman, Benjamin B., Kolson, Dennis L.
• Format: Journal Article
• Language: English
• Published: United States 01-08-2017
• Subjects: Antiviral Agents - pharmacology; Astrocytes - drug effects; Astrocytes - enzymology; Astrocytes - virology; Cells, Cultured; Cohort Studies; Cysteine Proteinase Inhibitors - pharmacology; Female; Fetus; HAND; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; HIV Infections - pathology; HIV‐associated neurocognitive disorders; Humans; immunoproteasome; interferon gamma; Interferon-gamma - pharmacology; Leupeptins - pharmacology; Lipopolysaccharides - pharmacology; Male; NAD(P)H Dehydrogenase (Quinone) - metabolism; Prefrontal Cortex - pathology; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; RNA - metabolism; Time Factors; immunoproteasome; interferon gamma; HAND; HIV-associated neurocognitive disorders
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23160

Induction of the detoxifying enzyme heme oxygenase‐1 (HO‐1) is a critical protective host response to cellular injury associated with inflammation and oxidative stress. We previously found that HO‐1 protein expression is reduced in brains of HIV‐infected individuals with HIV‐associated neurocognitive disorders (HAND) and in HIV‐infected macrophages, where this reduction associates with enhanced glutamate release and neurotoxicity. Because HIV‐infected macrophages are a small component of the cellular content of the brain, the reduction of macrophage HO‐1 expression likely accounts for a small portion of brain HO‐1 loss in HIV infection. We therefore investigated the contribution of astrocytes, the major pool of brain HO‐1. We identified immunoproteasome‐mediated HO‐1 degradation in astrocytes as a second possible mechanism of brain HO‐1 loss in HIV infection. We demonstrate that prolonged exposure of human fetal astrocytes to interferon‐gamma (IFNγ), an HIV‐associated CNS immune activator, selectively reduces expression of HO‐1 protein without a concomitant reduction in HO‐1 RNA, increases expression of immunoproteasome subunits, and decreases expression of constitutive proteasome subunits, consistent with a shift towards increased immunoproteasome activity. In HIV‐infected brain HO‐1 protein reduction also associates with increased HO‐1 RNA expression and increased immunoproteasome expression. Finally, we show that IFNγ treatment of astrocytic cells reduces HO‐1 protein half‐life in a proteasome‐dependent manner. Our data thus suggest unique causal links among HIV infection, IFNγ‐mediated immunoproteasome induction, and enhanced HO‐1 degradation, which likely contribute to neurocognitive impairment in HAND. Such IFNγ‐mediated HO‐1 degradation should be further investigated for a role in neurodegeneration in inflammatory brain conditions.
Brief Summary
Kovacsics et al. identify immunoproteasome degradation of heme oxygenase‐1 (HO‐1) in interferon gamma‐stimulated astrocytes as a plausible mechanism for the observed loss of HO‐1 protein expression in the brains of HIV‐infected individuals, which likely contributes to the neurocognitive impairment in HIV‐associated neurocognitive disorders.
Main Points
In HIV infection, decreased brain HO‐1 protein expression accompanies increased HO‐1 RNA and immunoproteasome expression
In astrocytes IFNγ increases immunoproteasome subunit expression and proteasome‐dependent HO‐1 protein degradation