Characterization and Genetic Analyses of New Genes Coding for NOD2 Interacting Proteins.
NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn's Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.
UMR1149, INSERM et Université Paris Diderot-Sorbonne Paris-Cité, 75018, Paris, France.
Raphaële
R
Thiébaut
INRA, UMR866, DMEM, Université de Montpellier, Montpellier, France.
Sophie
S
Esmiol
Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, "Cell Polarity, Cell signaling and Cancer - Equipe labellisée Ligue Contre le Cancer", Marseille, France.
Patrick
P
Lecine
UMR1149, INSERM et Université Paris Diderot-Sorbonne Paris-Cité, 75018, Paris, France.
Batoul
B
Mahfouz
Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, "Cell Polarity, Cell signaling and Cancer - Equipe labellisée Ligue Contre le Cancer", Marseille, France.
Aurelie
A
Hermant
Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR7313, 13397, Marseille, France.
Cendrine
C
Nicoletti
Aix Marseille Université, Centrale Marseille, CNRS, ISM2 UMR7313, 13397, Marseille, France.
Stephane
S
Parnis
CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, F-34094, France.|INSERM, U1191, Montpellier, F-34094, France.|Université de Montpellier, UMR-5203, Montpellier, F-34094, France.
Julie
J
Perroy
Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, "Cell Polarity, Cell signaling and Cancer - Equipe labellisée Ligue Contre le Cancer", Marseille, France.
Jean-Paul
JP
Borg
Fondation Jean Dausset, CEPH, Paris, France.
Leigh
L
Pascoe
UMR1149, INSERM et Université Paris Diderot-Sorbonne Paris-Cité, 75018, Paris, France.|Assistance Publique Hôpitaux de Paris, service de gastroentérologie pédiatrique, Hôpital Robert Debré, 75019, Paris, France.
Jean-Pierre
JP
Hugot
INRA, UMR866, DMEM, Université de Montpellier, Montpellier, France.
Vincent
V
Ollendorff
D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping
D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein