Immunoproteasomes

Ferrington, Deborah A.; Gregerson, Dale S.

doi:10.1016/b978-0-12-397863-9.00003-1

Cited by 328 publications

(235 citation statements)

References 130 publications

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“…This suggests that HIV infection does indeed drive the discordance between expression of HO-1 RNA and protein through a post-translational mechanism, and our in vitro astrocyte experiments suggest that this mechanism is immunoproteasome degradation of HO-1. While in this study we specifically identify and define IFNγ-induced immunoproteasome degradation of HO-1, other proinflammatory cytokines as well as oxidative stress induce the immunoproteasome (Ferrington and Gregerson 2012). Thus, HIV-associated CNS inflammation and oxidative stress in addition to elevated IFNγ is likely also contributing to immunproteasome induction and subsequent degradation of HO-1.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…These subunits assemble with the remaining proteasomal α and β subunits to form immunoproteasomes. Formation of immunoproteasomes increases the total proteolytic capacity of the UPS and improves the quantity and quality of the peptides generated for antigen presentation (41, 140). …”

Section: Beyond Quality Controlmentioning

confidence: 99%

Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

2013

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Cells use messenger RNAs (mRNAs) to ensure the accurate dissemination of genetic information encoded by DNA. Given that mRNAs largely direct the synthesis of a critical effector of cellular phenotype, i.e., proteins, tight regulation of both the quality and quantity of mRNA is a prerequisite for effective cellular homeostasis. Here, we review nonsense-mediated mRNA decay (NMD), which is the best-characterized posttranscriptional quality control mechanism that cells have evolved in their cytoplasm to ensure transcriptome fidelity. We use protein quality control as a conceptual framework to organize what is known about NMD, highlighting overarching similarities between these two polymer quality control pathways, where the protein quality control and NMD pathways intersect, and how protein quality control can suggest new avenues for research into mRNA quality control.

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“…No interaction between M and PSMB6 (which is replaced by LMP2 in the immunoproteasome) was detected, despite an important amino acid sequence identity between both proteins (42). This indicates that VSV M specifically targets the immunoproteasome and not the proteasome.…”

Section: Discussionmentioning

confidence: 90%

“…5A). These substitutions reduce the size of the S1 pocket and change the overall charge of the local environment from positive to neutral (42). To investigate if these changes had an effect on the interaction with VSV M, the LMP2 V20T and L45R point mutants and the V20T/L45R double mutant were constructed.…”

Section: Identification Of Lmp2 As a Binding Partner Of Vsv Matrix Prmentioning

confidence: 99%

Characterization of the Interaction between the Matrix Protein of Vesicular Stomatitis Virus and the Immunoproteasome Subunit LMP2

Beilstein

Obiang

Raux

et al. 2015

J Virol

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The matrix protein (M) of vesicular stomatitis virus (VSV) is involved in virus assembly, budding, gene regulation, and cellular pathogenesis. Using a yeast two-hybrid system, the M globular domain was shown to interact with LMP2, a catalytic subunit of the immunoproteasome (which replaces the standard proteasome catalytic subunit PSMB6). The interaction was validated by coimmunoprecipitation of M and LMP2 in VSV-infected cells. The sites of interaction were characterized. A single mutation of M (I96A) which significantly impairs the interaction between M and LMP2 was identified. We also show that M preferentially binds to the inactive precursor of LMP2 (bearing an N-terminal propeptide which is cleaved upon LMP2 maturation). Furthermore, taking advantage of a sequence alignment between LMP2 and its proteasome homolog, PSMB6 (which does not bind to M), we identified a mutation (L45R) in the S1 pocket where the protein substrate binds prior to cleavage and a second one (D17A) of a conserved residue essential for the catalytic activity, resulting in a reduction of the level of binding to M. The combination of both mutations abolishes the interaction. Taken together, our data indicate that M binds to LMP2 before its incorporation into the immunoproteasome. As the immunoproteasome promotes the generation of major histocompatibility complex (MHC) class I-compatible peptides, a feature which favors the recognition and the elimination of infected cells by CD8 T cells, we suggest that M, by interfering with the immunoproteasome assembly, has evolved a mechanism that allows infected cells to escape detection and elimination by the immune system. IMPORTANCEThe immunoproteasome promotes the generation of MHC class I-compatible peptides, a feature which favors the recognition and the elimination of infected cells by CD8 T cells. Here, we report on the association of vesicular stomatitis virus (VSV) matrix protein (M) with LMP2, one of the immunoproteasome-specific catalytic subunits. M preferentially binds to the LMP2 inactive precursor. The M-binding site on LMP2 is facing inwards in the immunoproteasome and is therefore not accessible to M after its assembly. Hence, M binds to LMP2 before its incorporation into the immunoproteasome. We suggest that VSV M, by interfering with the immunoproteasome assembly, has evolved a mechanism that allows infected cells to escape detection and elimination by the immune system. Modulating this M-induced immunoproteasome impairment might be relevant in order to optimize VSV for oncolytic virotherapy. V esicular stomatitis virus (VSV) is the prototype rhabdovirus and for years has been used as a model to study many aspects of the virus life cycle. Its negative-strand RNA genome of 11,161 nucleotides successively encodes the nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the RNAdependent RNA polymerase (L). The N, P, and L proteins are associated with the RNA molecule and compose the transcriptionally active nucleocapsid (NC). The NC is enveloped by...

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Immunoproteasomes

Cited by 328 publications

References 130 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

Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

Characterization of the Interaction between the Matrix Protein of Vesicular Stomatitis Virus and the Immunoproteasome Subunit LMP2

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