References of "Remouchamps, Caroline"
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See detailMethods to Assess the Activation of the Alternative (Noncanonical) NF-kappaB Pathway by Non-death TNF Receptors.
Remouchamps, Caroline ULg; Dejardin, Emmanuel ULg

in NF-kappa B: Methods and Protocols (2015)

The alternative or noncanonical NF-kappaB pathway regulates the generation of p52-containing NF-kappaB dimers (e.g., p52/RelB) through a partial degradation (called processing) of the precursor p100 into ... [more ▼]

The alternative or noncanonical NF-kappaB pathway regulates the generation of p52-containing NF-kappaB dimers (e.g., p52/RelB) through a partial degradation (called processing) of the precursor p100 into p52. This pathway is activated by a subset of non-death TNF receptor members, which ultimately activate two kinases: NIK (NF-kappaB-Inducing Kinase) and IKKalpha (Inhibitor of kappaB Kinase alpha). These kinases create a phosphodegron for the E3 ligase SCF-beta-TrCP that covalently binds K48-linked polyubiquitin chain onto p100 prior to its proteasomal processing. The resulting p52-containing complexes translocate into the nucleus to activate target genes involved in secondary lymphoid organ development, B cell survival or in osteoclastogenesis.We describe in this chapter straightforward methods to monitor the activation of the alternative NF-kappaB pathway. These methods uncover cytosolic and nuclear biochemical modifications of key proteins of the alternative NF-kappaB pathway required prior to the transcription of NF-kappaB target genes. [less ▲]

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See detailSpecific and Nonhepatotoxic Degradation of Nuclear Hepatitis B Virus cccDNA.
Lucifora, Julie; Xia, Yuchen; Reisinger, Florian et al

in Science (New York, N.Y.) (2014), 343

Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-alpha treatment can clear HBV but is limited by systemic side effects ... [more ▼]

Current antivirals can control but not eliminate hepatitis-B-virus (HBV), because HBV establishes a stable nuclear cccDNA. Interferon-alpha treatment can clear HBV but is limited by systemic side effects. Here, we describe how interferon-alpha can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-beta-receptor activation as a therapeutic alternative. Interferon-alpha and lymphotoxin-beta-receptor activation up-regulated APOBEC3A and 3B cytidine-deaminases, respectively, in HBV-infected cells, primary hepatocytes and human liver-needle biopsies. HBV-core protein mediated the interaction with nuclear cccDNA resulting in cytidine-deamination, apurinic/apyrimidinic site formation and finally cccDNA degradation that prevented HBV-reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases - e.g., by lymphotoxin-beta-receptor activation - allows development of new therapeutics that combined with existing antivirals may cure hepatitis B. [less ▲]

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See detailNoncanonical NF-kappaB Signaling Is Limited by Classical NF-kappaB Activity.
Gray, Carolyn M.; Remouchamps, Caroline ULg; McCorkell, Kelly A. et al

in Science signaling (2014), 7(311), 13

Precise regulation of nuclear factor kappaB (NF-kappaB) signaling is crucial for normal immune responses, and defective NF-kappaB activity underlies a range of immunodeficiencies. NF-kappaB is activated ... [more ▼]

Precise regulation of nuclear factor kappaB (NF-kappaB) signaling is crucial for normal immune responses, and defective NF-kappaB activity underlies a range of immunodeficiencies. NF-kappaB is activated through two signaling cascades: the classical and noncanonical pathways. The classical pathway requires inhibitor of kappaB kinase beta (IKKbeta) and NF-kappaB essential modulator (NEMO), and hypomorphic mutations in the gene encoding NEMO (ikbkg) lead to inherited immunodeficiencies, collectively termed NEMO-ID. Noncanonical NF-kappaB activation requires NF-kappaB-inducing kinase (NIK) and IKKalpha, but not NEMO. We found that noncanonical NF-kappaB was basally active in peripheral blood mononuclear cells from NEMO-ID patients and that noncanonical NF-kappaB signaling was similarly enhanced in cell lines lacking functional NEMO. NIK, which normally undergoes constitutive degradation, was aberrantly present in resting NEMO-deficient cells, and regulation of its abundance was rescued by reconstitution with full-length NEMO, but not a mutant NEMO protein unable to physically associate with IKKalpha or IKKbeta. Binding of NEMO to IKKalpha was not required for ligand-dependent stabilization of NIK or noncanonical NF-kappaB signaling. Rather, an intact and functional IKK complex was essential to suppress basal NIK activity in unstimulated cells. Despite interacting with IKKalpha and IKKbeta to form an IKK complex, NEMO mutants associated with immunodeficiency failed to rescue classical NF-kappaB signaling or reverse the accumulation of NIK. Together, these findings identify a crucial role for classical NF-kappaB activity in the suppression of basal noncanonical NF-kappaB signaling. [less ▲]

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See detailInduction of the Alternative NF-{kappa}B Pathway by Lymphotoxin {alpha}{beta} (LT{alpha}{beta}) Relies on Internalization of LT{beta} Receptor
Ganeff, Corine; Remouchamps, Caroline ULg; Boutaffala, Layla et al

in Molecular & Cellular Biology (2011), 21

Several tumor necrosis factor receptor (TNFR) family members activate both the classical and the alternative NF-κB pathways. However, how a single receptor engages these two distinct pathways is still ... [more ▼]

Several tumor necrosis factor receptor (TNFR) family members activate both the classical and the alternative NF-κB pathways. However, how a single receptor engages these two distinct pathways is still poorly understood. Using lymphotoxin β receptor (LTβR) as a prototype, we showed that activation of the alternative, but not the classical, NF-κB pathway relied on internalization of the receptor. Further molecular analyses revealed a specific cytosolic region of LTβR essential for its internalization, TRAF3 recruitment, and p100 processing. Interestingly, we found that dynamin-dependent, but clathrin-independent, internalization of LTβR appeared to be required for the activation of the alternative, but not the classical, NF-κB pathway. In vivo, ligand-induced internalization of LTβR in mesenteric lymph node stromal cells correlated with induction of alternative NF-κB target genes. Thus, our data shed light on LTβR cellular trafficking as a process required for specific biological functions of NF-κB. [less ▲]

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See detailBiology and Signal Transduction pathways of the Lymphotoxin-αβ/LTβR system
Remouchamps, Caroline ULg; Boutaffala, Layla; Ganeff, Corinne et al

in Cytokine & Growth Factor Reviews (2011), 22

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for ... [more ▼]

This review focuses on the biological functions and signalling pathways activated by Lymphotoxin α (LTα)/Lymphotoxin β (LTβ) and their receptor LTβR. Genetic mouse models shed light on crucial roles for LT/LTβR to build and to maintain the architecture of lymphoid organs and to ensure an adapted immune response against invading pathogens. However, chronic inflammation, autoimmunity, cell death or cancer development are disorders that occur when the LT/LTβR system is twisted. Biological inhibitors, such as antagonist antibodies or decoy receptors, have been developed and used in clinical trials for diseases associated to the LT/LTβR system. Recent progress in the understanding of cellular trafficking and NF-κB signaling pathways downstream of LTα/LTβ may bring new opportunities to develop therapeutics that target the pathological functions of these cytokines. [less ▲]

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See detailThe hidden function of NIK (NF-κB-Inducing Kinase) in cell death
Boutaffala, Layla; Bertrand, Mathieu; Remouchamps, Caroline ULg et al

Conference (2011)

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See detailTNFL–Induced p100 processing (TIPP) relies on the internalization of the cognate TNFR
Ganeff, Corinne; Galopin, Géraldine; Remouchamps, Caroline ULg et al

Conference (2010, January)

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See detailNF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening.
Mortier, Jeremie; Masereel, Bernard; Remouchamps, Caroline ULg et al

in Bioorganic & Medicinal Chemistry Letters (2010), 20(15), 4515-20

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the ... [more ▼]

As a wide variety of pro-inflammatory cytokines are involved in the development of rheumatoid arthritis (RA), there is an urgent need for the discovery of novel therapeutic strategies. Among these, the inhibition of the NF-kappaB inducing kinase (NIK), a key enzyme of the NF-kappaB alternative pathway activation, represents a potential interesting approach. In fact, NIK is involved downstream of many tumor necrosis factor receptors (TNFR) like CD40, RANK or LTbetaR, implicated in the pathogenesis of RA. But, up to now, the number of reported putative NIK inhibitors is extremely limited. In this work, we report a virtual screening (VS) study combining various filters including high-throughput docking using a 3D-homology model and ranking by using different scoring functions. This work led to the identification of two molecular fragments, 4H-isoquinoline-1,3-dione (5) and 2,7-naphthydrine-1,3,6,8-tetrone (6) which inhibit NIK with an IC(50) value of 51 and 90 microM, respectively. This study opens new perspectives in the field of the NF-kappaB alternative pathway inhibition. [less ▲]

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See detailPyrazolo[4,3-c]isoquinolines as potential inhibitors of NF-kappaB activation.
Mortier, Jeremie; Frederick, Raphael; Ganeff, Corinne et al

in Biochemical Pharmacology (2010), 79(10), 1462-72

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency ... [more ▼]

In this work, we aimed to build a 3D-model of NIK and to study the binding of pyrazolo[4,3-c]isoquinolines with a view to highlight the structural elements responsible for their inhibitory potency. However, in the course of this work, we unexpectedly found that the pyrazolo[4,3-c]isoquinolines initially reported as NIK inhibitors were neither inhibitors of this enzyme nor of the alternative NF-kappaB pathway, but were in fact inhibitors of another kinase, the TGF-beta activated kinase 1 (TAK1) which is involved in the classical NF-kappaB pathway. [less ▲]

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See detailTNFR-induced activation of MAP3K14/NIK enhances TNFR1-induced cell death
Boutafalla, Layla; Bertrand, Mathieu; Remouchamps, Caroline ULg et al

Conference (2010)

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See detailRole of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis airways
Verhaeghe, Catherine ULg; Remouchamps, Caroline ULg; Hennuy, Benoît ULg et al

in Biochemical Pharmacology (2007), 73(12), 1982-1994

in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular ... [more ▼]

in cystic fibrosis (CF) patients, pulmonary inflammation is a major cause of morbidity and mortality and may precede bacterial colonization. The aim of the present study was to investigate the molecular mechanisms underlying intrinsic inflammation in cystic fibrosis air-ways. Using different cystic fibrosis cell models, we first demonstrated that, beside a high constitutive nuclear factor of kappaB (NF-kappa B) activity, CF cells showed a higher activator protein-1 (AP-1) activity as compared to their respective control cells. Gene expression profiles, confirmed by RT-PCR and ELISA, showed over-expression of numerous NF-KB and AP-1-dependent pro-inflammatory genes in CF cells in comparison with control cells. Activation of NF-KB was correlated with higher inhibitor of kappa B kinase (IKK) activity. In addition, Bio-plex phosphoprotein assays revealed higher extracellular signal-regulated kinase (ERK) phosphorylation in CFT-2 cells. Inhibition of this kinase strongly decreased expression of pro-inflammatory genes coding for growth-regulated proteins (Gro-alpha, Gro-beta and Gro-gamma) and interleukins (IL-1 beta, IL-6 and IL-8). Moreover, inhibition of secreted interleukin-1 beta (IL-1 beta) and basic fibroblast growth factor (bFGF) with neutralizing antibodies reduced pro-inflammatory gene expression. Our data thus demonstrated for the first time that the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) at the plasma membrane leads to an intrinsic AP-1, in addition to NF-kappa B, activity and consequently to a pro-inflammatory state sustained through autocrine factors such as IL-1 beta and bFGF. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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