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See detailThe phosphorylation of RelA on Ser547 does not modulate NF-kB activation after TNFa treatment like after a genotoxic stress
Trussart, Charlotte ULg; Orban, Tanguy ULg; Di Valentin, Emmanuel ULg et al

Poster (2015, February 06)

NF-kB controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Numerous post-translational modifications of ... [more ▼]

NF-kB controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Numerous post-translational modifications of p65 modulating NF-kB transcriptional activity are known. We identified Ser547 as a new site of p65 phosphorylation targeted by ATM kinase, which coordinates the “DNA Damage Response” pathway in the event of DNA double-strand breaks. We demonstrated that the phosphorylation of Ser547 regulates the transcription of a sub-set of NF-κB dependent genes after genotoxic stress by modifying HDAC1 recruitment(1). Presently, we are investigating the role of this specific phosphorylation in an inflammatory context. We observe that the mutations of p65 (S547A or S547D) also affect the transcriptional potential of the NF-κB in a promoter specific manner after an exposition to TNFα and H2O2. The study of the molecular mechanism of this regulation after TNFα and H2O2 exposition are both in progress. [less ▲]

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See detailTSC2 and 14-3-3 proteins down-regulate a RIP3 dependent PDT-induced Necroptosis in Glioblastoma
Fettweis, Grégory ULg; Coupienne, Isabelle; Fillet, Marianne ULg et al

Poster (2014, October)

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See detailPromoter specific regulation of NF-kappaB by RelA phosphorylation on Ser547
Trussart, Charlotte ULg; Orban, Tanguy; Di Valentin, Emmanuel ULg et al

Poster (2014, August 29)

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory ... [more ▼]

NF-KB (p50/RelA) controls the expression of numerous genes involved in inflammation, survival, proliferation, and cancer initiation and progression. Both classical NF-kB activation by pro-inflammatory cytokines and ATM-dependant activation by DNA damage require IKK activation and IkBa degradation. Stimuli dependant phosphorylation of p65 controls its transcriptional potential often in a gene specific manner. Previously, we have reported a direct interaction between RelA and ATM, and, demonstrated the in vitro phosphorylation of Ser547 by this kinase. A comparative transcriptomic analysis performed in HEK cells expressing either p65WT or p65S547A identified several differentially transcribed genes after an etoposide treatment. Substitution of S547 to alanine does not affect p65 binding on the kB site of the modulated promoters but it reduces p65 interaction with HDAC1. The resulting enhanced histone H3 acetylation increases gene transcription at some specific promoters. Our data indicate that ATM regulates a sub-set of NF-kB dependent genes after a genotoxic stress by direct phosphorylation of p65. Presently, we are investigating the impact of p65S547A/D mutations after the addition of TNFa in Mefs p65 KO complemented with HA-p65WT or S547A/D. No differences are observed in the degradation of IkBb or the nuclear translocation of p50/p65. However both basal and TNFa-induced transcription levels of some kB dependent genes are elevated in Mefs expressing p65S547D. The role of ATM in NF-kB activation by TNFa is analyzed. [less ▲]

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See detailvCCL2, the third agonist ligand for the -arrestin-biased chemokine receptor CXCR7
Szpakowska, Martyna ULg; Derj, Anouar ULg; Counson, Manuel et al

Poster (2014, April)

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See detailPromotor specific regulation of NF-kappaB mediated transcription by the phosphorylation of p65 on Ser547.
Trussart, Charlotte ULg; Orban, Tanguy ULg; Sabatel, Hélène ULg et al

Poster (2014, January)

NF-kappaB (p50/p65) is an important regulator of gene transcription as it controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer ... [more ▼]

NF-kappaB (p50/p65) is an important regulator of gene transcription as it controls the expression of hundred of genes involved in inflammatory and innate responses, proliferation, survival, cancer initiation and progression. Several modes of NF-kappaB activation are known among which the classical pathway induced by pro-inflammatory cytokines and a complex atypical pathway induced by DNA damage. Both pathways converge on the IKK activation. The stimulidependent p65 phosphorylation on several serine can control its transcriptional potential either globally or often in a gene specific manner. Lately, we have reported a direct interaction between p65 and ATM and the in vitro phosphorylation of Ser547 by this kinase. A comparative transcriptomic analysis performed in HEK-293 cells expressing either p65WT or p65S547A identified several differentially transcribed genes (IL8, A20, SELE…) after an Etoposide treatment. Substitution of Ser547 to Ala does not affect p65 binding on the kappaB site of the IL8 promoter but it reduces p65 interaction with HDAC1 leading to a higher level of histone H3 acetylated on Lys9 and therefore a higher gene induction. These data indicate that ATM regulates a sub-set of NF-kappaB dependent genes after a genotoxic stress by direct phosphorylation of p65 (1). We are now investigating the impact of the S547A mutation in the context of an inflammatory response. Mefs p65KO expressing recombinant p65WT or p65S547A were treated with TNFalpha. No differences were observed in the kinetic of degradation of IkBa or the nuclear translocation of p65. The level of transcription of a few selected genes is presently under investigation. Contrary to another study, we did not observed any role of ATM in NF-kappaB activation by TNFalpha [less ▲]

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See detailMelanoma AntiGEn D2 (MAGED2) a new partner of the DNA damage response?
Pirlot, Céline ULg; Piette, Jacques ULg; Habraken, Yvette ULg

Poster (2014, January)

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. It is ubiquitously expressed and its overexpression in many cancers could make it a potential biomarker of tumor development and ... [more ▼]

MAGED2 belongs to the Melanoma AntiGEn (MAGE) family of proteins. It is ubiquitously expressed and its overexpression in many cancers could make it a potential biomarker of tumor development and metastasis formation. Actually, the only known function of this protein is its involvement in the p53 pathways. Indeed, MAGED2 could be a negative regulator of p53 and it increases apoptosis induced by TRAIL in a p53 dependent manner. Moreover, a phosphoproteomic experiment has shown that this protein is likely phosphorylated by ATM, ATR or DNA-PK after exposition to ionizing irradiation. These three kinases are implicated in the DNA damage response (DDR). Our lab showed by yeast two hybrids an interaction between MAGED2 and ATM. Thus, the aims of the project are to confirm and to find the function of this interaction in a DDR context. Current avenues of investigations include determining the impact of MAGED2 depletion and overexpression in the p53, NF-kappaB and cell cycle regulation following double strand break induced by etoposide treatment. Though this study we plan to confirm a new partner of ATM in the DDR pathway, which could be targeted to limit cancer progression and improve the chemotherapy relying on DNA damaging compounds. [less ▲]

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See detailDeletion of the ORF9p acidic cluster impairs the nuclear egress of Varicella-zoster virus capsids.
Riva, Laura ULg; Thiry, Marc ULg; Lebrun, Marielle ULg et al

in Journal of virology (2014)

The protein encoded by the ORF9 is essential for Varicella-zoster virus (VZV) replication. Previous studies documented its presence in the trans-Golgi network and its involvement in secondary envelopment ... [more ▼]

The protein encoded by the ORF9 is essential for Varicella-zoster virus (VZV) replication. Previous studies documented its presence in the trans-Golgi network and its involvement in secondary envelopment. In this work, we deleted the ORF9p acidic cluster, destroying its interaction with ORF47p and resulting in a nuclear accumulation of both proteins. This phenotype results to an accumulation of primary enveloped capsids in the perinuclear space, reflecting a capsid de-envelopment defect. [less ▲]

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See detailInflammasome NLRP3 et graisse viscerale.
Esser, Nathalie; Legrand-Poels, Sylvie ULg; Piette, Jacques ULg et al

in Revue medicale de Liege (2014), 69 Spec No

It is recognized that abdominal obesity is accompanied by a chronic low-grade inflammation that is involved in the pathogenesis of insulin resistance and type 2 diabetes. Metabolic syndrome and type 2 ... [more ▼]

It is recognized that abdominal obesity is accompanied by a chronic low-grade inflammation that is involved in the pathogenesis of insulin resistance and type 2 diabetes. Metabolic syndrome and type 2 diabetes are associated with an abnormal production of pro-inflammatory cytokines, an increased level of acute-phase proteins and an activation of inflammatory signalling pathways. These pro-inflammatory cytokines, mainly produced by adipose tissue macrophages, are involved in development of obesity-associated insulin resistance and in the progression from obesity to type 2 diabetes. Particularly, the interleukin-1 beta may play a key role through the activation of the NLRP3 inflammasome. Adipose tissue topography, more than the total amount of fat, may play an important pathogenic role. Indeed, the presence of metabolic abnormalities in obesity is associated with a deleterious immunological and inflammatory profile of visceral adipose tissue and with an increased activation of the NLRP3 inflammasome in macrophages infiltrating visceral adipose tissue. Targeting inflammation, especially NLRP3 inflammasome, may offer potential novel therapeutic perspectives in the prevention and treatment of type 2 diabetes. [less ▲]

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See detailInflammation as a link between obesity, metabolic syndrome and type 2 diabetes
ESSER, Nathalie ULg; Legrand, Sylvie ULg; Piette, Jacques ULg et al

in Diabetes Research & Clinical Practice (2014)

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic ... [more ▼]

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes. [less ▲]

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See detailObesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue
ESSER, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabetologia (2013), 56

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose ... [more ▼]

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals. Methods MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RTPCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals. Results We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c+CD206+ adipose tissue macrophages than in CD11c−CD206+ cells. Conclusions/interpretation The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype. [less ▲]

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See detailUnsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages
L'Homme, Laurent ULg; Esser, Nathalie ULg; Riva, Laura ULg et al

in Journal of Lipid Research (2013), 54

The NLRP3 inflammasome is involved in many obesity-associated diseases such as type 2 diabetes, atherosclerosis and gouty arthritis through its ability to induce IL-1β release. The molecular link between ... [more ▼]

The NLRP3 inflammasome is involved in many obesity-associated diseases such as type 2 diabetes, atherosclerosis and gouty arthritis through its ability to induce IL-1β release. The molecular link between obesity and inflammasome activation is still unclear but free fatty acids have been proposed as one triggering event. Here we reported opposite effects of saturated fatty acids (SFAs) compared to unsaturated fatty acids (UFAs) on NLRP3 inflammasome in human monocytes/macrophages. Palmitate and stearate, both SFAs, triggered IL-1β secretion in a caspase-1/ASC/NLRP3-dependent pathway. Unlike SFAs, the UFAs oleate and linoleate did not lead to IL-1β secretion. In addition, they totally prevented the IL-1β release induced by SFAs and, with less efficiency, by a broad range of NLRP3 inducers including nigericin, alum and MSU. UFAs did not affect the transcriptional effect of SFAs suggesting a specific effect on the NLRP3 activation. These results provide a new antiinflammatory mechanism of UFAs by preventing the activation of the NLRP3 inflammasome and therefore the IL-1β processing. By this way, UFAs might play a protective role in NLRP3-associated diseases. [less ▲]

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See detailRole of RIP3 in PDT-induced glioblastoma Cell Death
Fettweis, Grégory ULg; Coupienne, Isabelle; Fillet, Marianne ULg et al

Poster (2013, September 04)

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See detailDifférences d’activité de l’inflammasome NLRP3 entre sujets obèses avec et sans anomalies métaboliques
Esser, Nathalie ULg; L'Homme, Laurent ULg; DE ROOVER, Arnaud ULg et al

in Diabètes & Métabolism (2013, March), 39(suppl 1), 102

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See detailORF9p phosphorylation by ORF47p is crucial for the formation and egress of the Varicella-zoster virus (VZV) viral particles.
Riva, Laura ULg; Thiry, Marc ULg; BONTEMS, Sébastien ULg et al

in Journal of Virology (2013), 87(5), 2868-2881

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully ... [more ▼]

The role of the tegument during the herpesvirus lytic cycle is still not clearly established, particularly at the late phase of infection, when the newly produced viral particles need to be fully assembled before being released from the infected cell. The Varicella-zoster virus (VZV) protein coded by ORF9 (ORF9p) is an essential tegument protein and, even though its mRNA is the most expressed during the productive infection, little is known about its functions. Using a GalK positive/negative selection technique, we modified a BAC containing the complete VZV genome creating viruses expressing mutant versions of ORF9p.We showed that ORF9p is hyper-phosphorylated during the infection, especially through its interaction with the viral Ser/Thr kinase ORF47p; we identified a consensus site within ORF9p recognized by ORF47p and demonstrated its importance for ORF9p phosphorylation. Strikingly, an ultra-structural analysis revealed that the mutation of this consensus site (Glutamate 85 to Arginine) strongly affects viral assembly and release, reproducing ORF47 kinase dead VZV phenotype. It also slightly diminishes the infectivity towards immature dendritic cells. Taken together, our results identify ORF9p as a new viral substrate of ORF47p and suggest a determinant role of this phosphorylation for viral infectivity, especially during the process of viral particle formation and egress. [less ▲]

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