Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes

A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis

Colleen E. Kovacsics, Alexander J. Gill, Surendra S. Ambegaokar, Benjamin Gelman, Dennis L. Kolson

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1264-1277
Number of pages14
JournalGLIA
Volume65
Issue number8
DOIs
StatePublished - Aug 1 2017

Fingerprint

Heme Oxygenase-1
Astrocytes
Interferons
HIV
Interferon-gamma
Brain
HIV Infections
Macrophages
Proteasome Endopeptidase Complex
Proteins
RNA
Enzyme Induction

Keywords

  • HAND
  • HIV-associated neurocognitive disorders
  • immunoproteasome
  • interferon gamma

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes : A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis. / Kovacsics, Colleen E.; Gill, Alexander J.; Ambegaokar, Surendra S.; Gelman, Benjamin; Kolson, Dennis L.

In: GLIA, Vol. 65, No. 8, 01.08.2017, p. 1264-1277.

Research output: Contribution to journalArticle

Kovacsics, Colleen E. ; Gill, Alexander J. ; Ambegaokar, Surendra S. ; Gelman, Benjamin ; Kolson, Dennis L. / Degradation of heme oxygenase-1 by the immunoproteasome in astrocytes : A potential interferon-γ-dependent mechanism contributing to HIV neuropathogenesis. In: GLIA. 2017 ; Vol. 65, No. 8. pp. 1264-1277.
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