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See detailLa protéine JNKBP1 agit comme un régulateur négatif de la signalisation de NOD2 en inhibant son processus d’oligomérisation
Lecat, Aurore ULg

Doctoral thesis (2012)

Le récepteur cytoplasmique NOD2 est l'un des membres les mieux caractérisés de la famille des NLRs. NOD2 est capable de détecter le muramyldipeptide (MDP), un composant de la paroi bactérienne, ce qui ... [more ▼]

Le récepteur cytoplasmique NOD2 est l'un des membres les mieux caractérisés de la famille des NLRs. NOD2 est capable de détecter le muramyldipeptide (MDP), un composant de la paroi bactérienne, ce qui induit les différentes cascades de signalisation conduisant à l'activation de NF-κB, des MAPKs et de l'autophagie. Ces voies contribuent à une réponse immunitaire innée et adaptative efficace. La perte de fonction des mutants NOD2 a été associée à une plus grande susceptibilité à la maladie de Crohn, ce qui souligne l'importance physiologique de la régulation de l'activité de NOD2. Nous avons effectué une étude par une approche protéomique pour rechercher de nouveaux régulateurs de NOD2. Nous avons généré un modèle cellulaire pour cette étude, les cellules HEK293GNV. Nous avons identifié plusieurs nouveaux partenaires de NOD2, dont la protéine JNKBP1 (c-Jun N-terminal kinase binding protein 1), une protéine scaffold caractérisée par un domaine WD40 en amino-terminal. Nous avons aussi débuté la caractérisation d’autres protéines appartenant aux complexes NOD2 purifiés comme ROCK2 (Rho activated kinase 2) et HDAC5 (Histone deacetylase 5). Au vu de nos premiers résultats, les protéines ROCKs sembleraient être des activateurs de la voie NOD2. Nous nous sommes principalement consacrés à l’étude de JNKBP1 qui a été identifiée, en 1999, comme un partenaire et un régulateur positif de JNK. Nous avons montré que JNKBP1 via son domaine WD40, se lie à NOD2 suite à l’activation par le MDP. Cette interaction atténuait l'activation de NF-κB dépendante de NOD2, la synthèse de l'IL-8 et l’activité antibactérienne de NOD2. JNKBP1 exerçait son effet répresseur en perturbant l’oligomérisation NOD2 et la phosphorylation de la tyrosine de RIP2 : deux étapes nécessaires à la signalisation en aval. En outre, nous avons montré que JNKBP1 et NOD2 étaient exprimées dans l'épithélium intestinal humain et dans les cellules immunitaires recrutées dans la lamina propria, ce qui suggère que JNKBP1 contribuerait au maintien de l'homéostasie intestinale dépendante de NOD2. [less ▲]

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See detailThe inositol phosphatase SHIP-1 inhibits NOD2-induced NF-κB activation by disturbing the interaction of XIAP with RIP2
Condé, Claude ULg; Rambout, Xavier ULg; Lebrun, Marielle ULg et al

in PLoS ONE (2012)

SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a ... [more ▼]

SHIP-1 is an inositol phosphatase predominantly expressed in hematopoietic cells. Over the ten past years, SHIP-1 has been described as an important regulator of immune functions. Here, we characterize a new inhibitory function for SHIP-1 in NOD2 signaling. NOD2 is a crucial cytoplasmic bacterial sensor that activates proinflammatory and antimicrobial responses upon bacterial invasion. We observed that SHIP-1 decreases NOD2-induced NF-κB activation in macrophages. This negative regulation relies on its interaction with XIAP. Indeed, we observed that XIAP is an essential mediator of the NOD2 signaling pathway that enables proper NF-κB activation in macrophages. Upon NOD2 activation, SHIP-1 C-terminal proline rich domain (PRD) interacts with XIAP, thereby disturbing the interaction between XIAP and RIP2 in order to decrease NF-κB signaling. [less ▲]

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See detailThe c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Somja, Joan ULg et al

in Journal of Biological Chemistry (2012), 287(35), 29213-26

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]

NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]

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See detailidentification of new parterns of the NOD2 protein
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Fillet, Marianne ULg et al

Poster (2011, January 27)

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See detailNOD2 interactome
Lecat, Aurore ULg; Di Valentin, Emmanuel ULg; Fillet, Marianne ULg et al

Poster (2010, January 28)

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See detailThe protein Nod2: an innate receptor more complex than previously assumed.
Lecat, Aurore ULg; Piette, Jacques ULg; Legrand-Poels, Sylvie ULg

in Biochemical Pharmacology (2010), 80(12), 2021-31

For almost 10 years, Nod2 has been known as a cytosolic innate receptor able to sense peptidoglycan from Gram-positive and -negative bacteria and to trigger RIP2- and NF-kappaB-mediated pro-inflammatory ... [more ▼]

For almost 10 years, Nod2 has been known as a cytosolic innate receptor able to sense peptidoglycan from Gram-positive and -negative bacteria and to trigger RIP2- and NF-kappaB-mediated pro-inflammatory and antibacterial response. Mutations in the gene encoding Nod2 in humans have been associated with Crohn's disease (CD). Mechanisms by which Nod2 variants can lead to CD development are still under investigation. The most admitted hypothesis suggests that the impaired function of Nod2 variants in intestinal epithelial and phagocytic cells results in deficiencies in epithelial-barrier function which subsequently lead to increased bacterial invasion and inflammation at intestinal sites. Very recent results have just reinforced this hypothesis by demonstrating that Nod2 wild-type (unlike Nod2 variants) could mediate autophagy, allowing an efficient bacterial clearance and adaptative immune response. Other recent data have attributed new roles to Nod2. Indeed, Nod2 has been shown to activate antiviral innate immune responses involving IRF3-dependent IFN-beta production after viral ssRNA recognition through a RIP2-independent mechanism requiring the mitochondrial adaptor protein MAVS. Recently, Nod2 has been also shown to be exquisitely tuned to detect mycobacterial infections and mount a protective immunity against these pathogens. [less ▲]

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