The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network
The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network
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DOI：
10.1007/s00109-008-0307-5
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发表时间：
2008-04-01
影响因子：
4.7
通讯作者：
Weiner, J.
中科院分区：
文献类型：
--
作者：
Friedrichs, Frauke;Henckaerts, Liesbet;Weiner, J.
Diss Large Homolog 5(DLG5)是膜相关鸟氨酸蛋白(Maguk)家族中的一员，与克罗恩病(CD)有关，但其在炎症性肠病发病机制中的作用尚存争议。在这里，我们使用序列比较和系统发育分析的方法来分析DLG5基因及其蛋白产物。我们发现了一个5‘外显子，该外显子编码一个N-末端caspase募集结构域(CARD)，并在实验上证实了它在结肠组织中的表达。DLG5与含有2(NOD2)的核苷酸结合寡聚区共享这个新的结构域；NOD2是在遗传学研究中发现的第一个CD易感因子。一项广泛的系统发育分析重新定义了Maguk蛋白的家族组织：DLG5与CARD10、CARD11和CARD14密切相关，CARD10、CARD11和CARD14是启动促炎因子kappa B信号的含有CARD10、CARD11和CARD14的蛋白，而不是DLG1-4，后者以前被认为是最接近的相关蛋白。因此，我们建议将DLG5重新命名，以便在其系统发育和功能上下文中正确地注释该基因。我们的研究提供了支架蛋白DLG5属于CARD蛋白家族的证据。因此，DLG5可能作为宿主防御机制的一部分参与调节NFkB的激活或caspase的激活。由于在卡片介导的通路之间存在严重的串扰，CD易感基因NOD2和DLG5可能在功能上相互作用，从而导致CD风险。
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 NF kappa B 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.