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Glutathione and Glutathione Transferase Omega 1 as Key Posttranslational Regulators in Macrophages

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  • Authors: Mark M. Hughes1, Anne F. McGettrick2, Luke A. J. O’Neill3
  • Editor: Siamon Gordon4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland; 2: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland; 3: School of Biochemistry and Immunology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin 2, Ireland; 4: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
  • Received 26 July 2016 Accepted 23 November 2016 Published 20 January 2017
  • Luke A. J. O’Neill, laoneill@tcd.ie
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  • Abstract:

    Macrophage activation during phagocytosis or by pattern recognition receptors, such as Toll-like receptor 4, leads to the accumulation of reactive oxygen species (ROS). ROS act as a microbicidal defense mechanism, promoting clearance of infection, allowing for resolution of inflammation. Overproduction of ROS, however, overwhelms our cellular antioxidant defense system, promoting oxidation of protein machinery, leading to macrophage dysregulation and pathophysiology of chronic inflammatory conditions, such as atherosclerosis. Here we will describe the role of the antioxidant tripeptide glutathione (GSH). Until recently, the binding of GSH, termed glutathionylation, was only considered to maintain the integrity of cellular components, limiting the damaging effects of an aberrant oxidative environment. GSH can, however, have positive and negative regulatory effects on protein function in macrophages. GSH regulates protein secretion, driving tumor necrosis factor α release, hypoxia-inducible factor-1α stability, STAT3 phosphorylation, and caspase-1 activation in macrophages. GSH also plays a role in host defense against , modifying the key virulence protein PrfA in infected macrophages. We will also discuss glutathione transferase omega 1, a deglutathionylating enzyme recently shown to play a role in many aspects of macrophage activity, including metabolism, NF-κB activation, and cell survival pathways. Glutathionylation is emerging as a key regulatory event in macrophage biology that might be susceptible to therapeutic targeting.

  • Citation: Hughes M, McGettrick A, O’Neill L. 2017. Glutathione and Glutathione Transferase Omega 1 as Key Posttranslational Regulators in Macrophages. Microbiol Spectrum 5(1):MCHD-0044-2016. doi:10.1128/microbiolspec.MCHD-0044-2016.

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/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0044-2016
2017-01-20
2017-05-24

Abstract:

Macrophage activation during phagocytosis or by pattern recognition receptors, such as Toll-like receptor 4, leads to the accumulation of reactive oxygen species (ROS). ROS act as a microbicidal defense mechanism, promoting clearance of infection, allowing for resolution of inflammation. Overproduction of ROS, however, overwhelms our cellular antioxidant defense system, promoting oxidation of protein machinery, leading to macrophage dysregulation and pathophysiology of chronic inflammatory conditions, such as atherosclerosis. Here we will describe the role of the antioxidant tripeptide glutathione (GSH). Until recently, the binding of GSH, termed glutathionylation, was only considered to maintain the integrity of cellular components, limiting the damaging effects of an aberrant oxidative environment. GSH can, however, have positive and negative regulatory effects on protein function in macrophages. GSH regulates protein secretion, driving tumor necrosis factor α release, hypoxia-inducible factor-1α stability, STAT3 phosphorylation, and caspase-1 activation in macrophages. GSH also plays a role in host defense against , modifying the key virulence protein PrfA in infected macrophages. We will also discuss glutathione transferase omega 1, a deglutathionylating enzyme recently shown to play a role in many aspects of macrophage activity, including metabolism, NF-κB activation, and cell survival pathways. Glutathionylation is emerging as a key regulatory event in macrophage biology that might be susceptible to therapeutic targeting.

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Figures

Image of FIGURE 1
FIGURE 1

GSH synthesis pathway in mammalian cells. GSH is exported from the cell to the extracellular environment via a glutathione transporter ( 1 ). Extracellular GSH is targeted by γ-glutamylpeptidase (GGT), transferring the γ-glutamyl component of GSH to an amino acid, forming γ-glutamylamino acid and cysteinylglycine ( 2 ). Cysteinylglycine is further cleaved by dipeptidase (DP) into the amino acids cysteine and glycine ( 3 ). γ-glutamylamino acid, cysteine, and glycine reenter the cell via an amino acid transporter ( 4 ). Release of the amino acid component of γ-glutamylamino acid forms 5-oxoproline, which is further converted to glutamate in an ATP-dependent process ( 5 ). Newly formed glutamate and cysteine are ligated into γ-glutamylcysteine via glutamate cysteine ligase (GCL) in an ATP-dependent process ( 6 ). γ-Glutamylcysteine and glycine are ligated via GSH synthase to re-form GSH ( 7 ).

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 2
FIGURE 2

Cellular roles of GSH. Oxidative stress can be induced by many exogenous factors, including LPS, or endogenously by the mitochondrial electron transport chain. ROS can build up within the cell, in the form of O and HO, which damages organelles and results in 4-HNE production. 4-HNE can promote lipid peroxidation and caspase-3 activation. The redox enzyme GSTA4-4 can target 4-HNE, utilizing GSH to prevent lipid peroxidation and maintain homeostasis. O and HO can be reduced via redox enzymes SOD1 and glutathione peroxidase 4 (GPx4), respectively. Both enzymes utilize GSH to remove ROS, forming glutathione disulfide (GSSG). GSSG can then be reduced to GSH by glutathione reductase (GR).

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 3
FIGURE 3

GSH-dependent inhibition of caspase-1 activity. (Left) Production of ROS from mitochondria drives NLRP3 inflammasome activation, producing mature IL-1β and IL-18 via caspase-1 activity. (Right) Over time, ROS accumulation leads to GSH binding to Cys362 and Cys397 on caspase-1, inhibiting caspase-1 catalytic activity. Oxidizing agents, such as superoxide and hydrogen peroxide, can induce glutathionylation of caspase-1, preventing cleavage of pro-IL-1β and pro-IL-18.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 4
FIGURE 4

HIF1α protein is stabilized by glutathionylation. MS revealed two redox-sensitive cysteines that undergo glutathionylation, Cys520 in humans or Cys533 in mice. Ischemia-reperfusion of Glrx-deficient mice showed improved hind limb revascularization and increased HIF1α levels. HIF1α stability was increased due to deficiency of Glrx, increasing expression of VEGF-A and blood flow recovery.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 5
FIGURE 5

Glutathionylation of STAT3 prevents STAT3 phosphorylation and nuclear translocation. Activation of the IL-6 receptor by the cytokine IL-6 drives phosphorylation of JAK2. JAK2 subsequently phosphorylates STAT3, promoting nuclear translocation for upregulation of STAT3-dependent gene transcription. The oxidant diamide induces glutathionylation of two redox-sensitive cysteines on STAT3, Cys328 and Cys542, preventing JAK2-dependent STAT3 phosphorylation and nuclear translocation.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 6
FIGURE 6

GSH acts as a cofactor to promote virulence gene expression by . Macrophage infection by is dependent on the master virulence gene transcription factor PrfA. PrfA transcribes ActA, an actin-mobility protein that promotes virulence success of . synthesizes its own GSH with the enzyme gshF. PrfA is only active when GSH binds as a cofactor, an event essential for virulence.

Source: microbiolspec January 2017 vol. 5 no. 1 doi:10.1128/microbiolspec.MCHD-0044-2016
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Image of FIGURE 7
FIGURE 7

GSTO1-1 regulates macrophage responses to cellular processes. GSTO1-1 protects macrophages from AFB-induced apoptosis. GSTO1-1 is also essential for LPS action in macrophages, including translocation of NF-κB to the nucleus, increased glycolysis, elevated TCA cycle intermediate succinate levels, NOX-1 activation, and subsequent ROS induction. GSTO1-1 is therefore likely to regulate components in the TLR4 signaling pathway.

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