title: The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network.
abstract: Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn's disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5' exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFkappaB signalling, but not to DLG1-4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk.
authors.affiliation: Department of Genetic Epidemiology, Leibniz-Institute for Arteriosclerosis Research, University Münster, Münster, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Friedrichs
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Torsten
authors.initials: T
authors.lastname: Kucharzik
authors.forename: Tanja
authors.initials: T
authors.lastname: Seehafer
authors.forename: Maren
authors.initials: M
authors.lastname: Möller-Krull
authors.forename: Erich
authors.initials: E
authors.lastname: Bornberg-Bauer
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: January
authors.initials: J
authors.lastname: Weiner
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001483:Base Sequence; D019295:Computational Biology; D003424:Crohn Disease / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism
chemical_list: C114461:DLG5 protein, human; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins