SYNCRIP-Dependent <i>Nox2</i> mRNA Destabilization Impairs ROS Formation in M2-Polarized Macrophages

Kuchler, Laura; Giegerich, Annika K.; Sha, Lisa K.; Knape, Tilo; Wong, Michael Sze Ka; Schröder, Katrin; Brandes, Ralf P.; Heide, Heinrich; Wittig, Ilka; Brüne, Bernhard; Knethen, Andreas von

doi:10.1089/ars.2013.5760

Cited by 38 publications

(28 citation statements)

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“…[2][3][4][5][6][7][8][9][10] Biological roles of SYNCRIP include, in addition to APOBEC1 regulation, 1 viral RNA synthesis and replication, 5-7 neuronal morphogenesis and synaptic transmission, 2,8-10 translation of the tumor suppressor p53 and colon cancer proliferation, 11 modulation of circadian oscillation, 3,4 regulation of insulin receptor activation and internalization, 12 and macrophage polarization. 13…”

Section: Introductionmentioning

confidence: 99%

The acidic domain is a unique structural feature of the splicing factor SYNCRIP

et al. 2016

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The splicing factor SYNCRIP (hnRNP Q) is involved in viral replication, neural morphogenesis, modulation of circadian oscillation, and the regulation of the cytidine deaminase APOBEC1. It consists of three globular RNA-recognition motifs (RRM) domains flanked by an N-terminal acid-rich acidic sequence segment domain (AcD 12-97 ) and a C-terminal domain containing an arginine-glycine-rich sequence motif (RGG/RXG box), which are located near to the N-and C-terminals, respectively. The acid-rich sequence segment is unique to SYNCRIP and the closely related protein hnRNP R, and is involved in interactions with APOBEC1. Here, we show that while AcD 12-97 does not form a globular domain, structure-based annotation identified a self-folding globular domain with an all a-helix architecture, AcD 24-107 . The NMR structure of AcD 242107 is fundamentally different from previously reported AcD molecular models. In addition to negatively charged surface areas, it contains a large hydrophobic cavity and a positively charged surface area as potential epitopes for intermolecular interactions.

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Section: Introductionmentioning

confidence: 99%

The acidic domain is a unique structural feature of the splicing factor SYNCRIP

et al. 2016

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“…Incubations of Bone Marrow-derived Murine Macrophages (BMDM) and Cytotoxicity Assay-BMDM were generated from total bone marrow of 12-week-old Nrf2 ϩ/ϩ and Nrf2 Ϫ/Ϫ mice in the C57BL/6J background as described previously (24). Compounds were prepared as DMSO stock solutions and further diluted in growth medium (RPMI medium (Gibco) containing 10% heat-inactivated FBS (PAA Laboratories)).…”

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confidence: 99%

Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling

Winkel

Engel

Margerie

et al. 2015

Journal of Biological Chemistry

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The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a K d of ϳ6 M, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 M RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.The transcription factor NF-E2-related factor 2 (Nrf2) 2 is a promising target for the treatment of oxidative and inflammatory stress-related disorders, such as neurodegenerative and microvascular diseases (1-5). Nrf2 regulates the expression of several cytoprotective anti-oxidative and anti-inflammatory proteins by binding to the cis-acting antioxidant response element (ARE) within gene promoters. Nrf2 itself is regulated by the kelch-like ECH-associated protein 1 (Keap1), which is a substrate recognition subunit for a cullin3-based ubiquitin E3 ligase and functions as a sensor for oxidative and electrophilic stress. Structural elements of the Keap1 protein include the C-terminal Nrf2-binding kelch domain, the intervening region, and the broad complex-Tramtrack-Bric-a-Brac domain. Keap1 binds as a dimer via its two Kelch domains to one molecule of Nrf2, specifically to the high affinity ETGE and the low affinity DLG motives at the N terminus of Nrf2. Without stressors, this leads to the ubiquitinylation and subsequent proteolytic degradation of the transcription factor. In the presence of oxidative or electrophilic stress, cysteine residues within the intervening region and broad complex-Tramtrack-Bric-a-Brac domain of Keap1 become modified. According to the hinge and latch model, this weakens the interaction between Keap1 and the DLG motif of Nrf2 but does not lead to a release of Nrf2 (6, 7). The conformation cycling model postulates a stabilization of the Keap1/Nrf2 interaction by the Keap1 modifica...

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“…Pathogenic conditions linked with chronic inflammation may lead to sepsis like conditions [26][27][28][29] . Interestingly, progression of sepsis apart from giving rise to M1 type macrophages also engages M2 polarized macrophages [30] with an alternative state of activation in anti-inflammatory cytokine secretion. These anti-inflammatory cytokines for example, TGF-β and IL10, while promoting resolution of inflammation and tissue repair, also endorse immunosuppression [31][32][33][34][35] .…”

Section: Functionsmentioning

confidence: 99%

Macrophage as a mediator of immune response: Sustenance of immune homeostasis

2015

Macrophage

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Macrophages have evolved as a key player in our immune system. As macrophages remain groomed to combat invasions by pathogens they also exhibit distinct polarized (M1/M2) states while adapting to the local environmental milieu. Detailed molecular mechanisms governing the prevalence of the usual steady state as well as altered (M1/M2) homeostasis programs under normal and pathogenic conditions remain to be deciphered. In this review, we have discussed the significance of immune homeostasis in macrophages and the involvement of Wnt -Frizzled signalling therein. Overall this review throws light upon some important questions related to the immune homeostasis scheme, answers to which will offer new insight in the field of immunology.

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SYNCRIP-Dependent Nox2 mRNA Destabilization Impairs ROS Formation in M2-Polarized Macrophages

Cited by 38 publications

References 59 publications

The acidic domain is a unique structural feature of the splicing factor SYNCRIP

The acidic domain is a unique structural feature of the splicing factor SYNCRIP

Characterization of RA839, a Noncovalent Small Molecule Binder to Keap1 and Selective Activator of Nrf2 Signaling

Macrophage as a mediator of immune response: Sustenance of immune homeostasis

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