Regulation of the Proteasome: Evaluating the Lung Proteasome as a New Therapeutic Target

Meiners, Silke; Keller, Ilona; Caniard, Anne

doi:10.1089/ars.2013.5798

Cited by 36 publications

(32 citation statements)

References 203 publications

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“…The progressive loss of β5 and β1 at each time point suggests that the loss of these constitutive subunits combined with the increased expression of the immunoproteasome subunits may account for the reduction of HO-1 protein expression. This is consistent with previously reported IFNγ-driven replacement of constitutive proteasomes by immunoproteasomes (Groettrup et al 2001; Heink et al 2005; Meiners et al 2014; Rivett et al 2001; Tanaka 2013) and it is further consistent with a role for the immunoproteasome in mediating HO-1 protein loss with IFNγ treatment.…”

Section: Resultssupporting

confidence: 93%

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

Kovacsics

Gill

Ambegaokar

et al. 2017

Glia

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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.

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Section: Resultssupporting

confidence: 93%

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

Kovacsics

Gill

Ambegaokar

et al. 2017

Glia

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“…In conclusion, our findings demonstrate rapid remodeling of proteasome complexes and support the building block concept in which proteasome activators rapidly assemble into distinct proteasome complexes according to cellular needs (30). Identification of novel compounds that specifically interfere with PA28␥-or PA200-mediated activation of 20S proteasomes should help to unravel the exact cellular roles of these alternative complexes and may also prove to be suitable to manipulate proteasome subcomplexes in a more specific fashion.…”

Section: Discussionsupporting

confidence: 72%

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Welk

Coux

Kleene

et al. 2016

Journal of Biological Chemistry

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The proteasome is an intracellular protease complex consisting of the 20S catalytic core and its associated regulators, including the 19S complex, PA28␣␤, PA28␥, PA200, and PI31. Inhibition of the proteasome induces autoregulatory de novo formation of 20S and 26S proteasome complexes. Formation of alternative proteasome complexes, however, has not been investigated so far. We here show that catalytic proteasome inhibition results in fast recruitment of PA28␥ and PA200 to 20S and 26S proteasomes within 2-6 h. Rapid formation of alternative proteasome complexes did not involve transcriptional activation of PA28␥ and PA200 but rather recruitment of preexisting activators to 20S and 26S proteasome complexes. Recruitment of proteasomal activators depended on the extent of active site inhibition of the proteasome with inhibition of ␤5 active sites being sufficient for inducing recruitment. Moreover, specific inhibition of 26S proteasome activity via siRNA-mediated knockdown of the 19S subunit RPN6 induced recruitment of only PA200 to 20S proteasomes, whereas PA28␥ was not mobilized. Here, formation of alternative PA200 complexes involved transcriptional activation of the activator. Alternative proteasome complexes persisted when cells had regained proteasome activity after pulse exposure to proteasome inhibitors. Knockdown of PA28␥ sensitized cells to proteasome inhibitor-mediated growth arrest. Thus, formation of alternative proteasome complexes appears to be a formerly unrecognized but integral part of the cellular response to impaired proteasome function and altered proteostasis.The proteasome, one of the main proteolytic systems of the cell, is essential for maintenance of protein homeostasis and thus of cellular functions. The proteolytic activity of this multicatalytic protease resides inside the 20S core particle, built of four stacked rings of seven ␣ and ␤ subunits with ␣ 7

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“…The function of the proteasome, which is responsible for the ubiquitin-mediated destruction of proteins, may be impaired by environmental challenges, disrupting proteostasis and contributing to COPD pathogenesis (57). Consistent with these findings, the function of the UPS declines during aging and may contribute to the development of disease (58).…”

Section: Maintenance Of the Aging Proteome Through Proteostasismentioning

confidence: 77%

Blue Journal Conference. Aging and Susceptibility to Lung Disease

Thannickal

Murthy

Balch

et al. 2015

Am J Respir Crit Care Med

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155

128

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The aging of the population in the United States and throughout the developed world has increased morbidity and mortality attributable to lung disease, while the morbidity and mortality from other prevalent diseases has declined or remained stable. Recognizing the importance of aging in the development of lung disease, the American Thoracic Society (ATS) highlighted this topic as a core theme for the 2014 annual meeting. The relationship between aging and lung disease was discussed in several oral symposiums and poster sessions at the annual ATS meeting. In this article, we used the input gathered at the conference to develop a broad framework and perspective to stimulate basic, clinical, and translational research to understand how the aging process contributes to the onset and/or progression of lung diseases. A consistent theme that emerged from the conference was the need to apply novel, systems-based approaches to integrate a growing body of genomic, epigenomic, transcriptomic, and proteomic data and elucidate the relationship between biologic hallmarks of aging, altered lung function, and increased susceptibility to lung diseases in the older population. The challenge remains to causally link the molecular and cellular changes of aging with age-related changes in lung physiology and disease susceptibility.

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Regulation of the Proteasome: Evaluating the Lung Proteasome as a New Therapeutic Target

Cited by 36 publications

References 203 publications

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

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

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

Blue Journal Conference. Aging and Susceptibility to Lung Disease

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