Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis.
Title | Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes: A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Kovacsics, CE, Gill, AJ, Ambegaokar, SS, Gelman, BB, Kolson, DL |
Journal | Glia |
Volume | 65 |
Issue | 8 |
Pagination | 1264-1277 |
Date Published | 2017 08 |
ISSN | 1098-1136 |
Keywords | Antiviral Agents, Astrocytes, Cells, Cultured, Cohort Studies, Cysteine Proteinase Inhibitors, Female, Fetus, Heme Oxygenase-1, HIV Infections, Humans, Interferon-gamma, Leupeptins, Lipopolysaccharides, Male, NAD(P)H Dehydrogenase (Quinone), Prefrontal Cortex, Proteasome Endopeptidase Complex, RNA, Time Factors |
Abstract | 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. |
DOI | 10.1002/glia.23160 |
Alternate Journal | Glia |
PubMed ID | 28543773 |
PubMed Central ID | PMC5739592 |
Grant List | F30 MH102120 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States T32 NS007180 / NS / NINDS NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States R01 MH104134 / MH / NIMH NIH HHS / United States R01 NS072005 / NS / NINDS NIH HHS / United States R01 MH095671 / MH / NIMH NIH HHS / United States U01 AI069911 / AI / NIAID NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States P30 MH092177 / MH / NIMH NIH HHS / United States U24 MH100930 / MH / NIMH NIH HHS / United States R01 MH111389 / MH / NIMH NIH HHS / United States |