A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways
A short isoform of NOD2/CARD15, NOD2-S, is an endogenous inhibitor of NOD2/receptor-interacting protein kinase 2-induced signaling pathways
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DOI：
10.1073/pnas.0505423103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Schreiber, S
中科院分区：
文献类型：
--
作者：
Rosenstiel, P;Huse, K;Schreiber, S
基因剪接模式的改变有助于通过产生内源性抑制或激活分子来调节基因功能。核苷酸结合和寡聚化结构域(NOD)2是细菌细胞壁成分的胞内受体，在启动对细胞侵袭性病原体的免疫反应中发挥重要作用。NOD2的过表达使肠上皮细胞对细菌细胞壁成分敏感，激活促炎转录因子NF-kappa B，并诱导随后的趋化细胞因子IL-8的释放。在这里，我们评估了NOD2转录异构体NOD2-S的调控和功能，该转录异构体是由跳过第三外显子产生的，该外显子编码在第二个caspase招募(CARD)结构域内截断的蛋白质。NOD2-S在人结肠中优先表达，并被抗炎细胞因子IL-10上调。NOD2-S过表达下调NOD2诱导的核因子-kappaB活化和IL-8释放。此外，NOD2-S还干扰NOD2及其接头分子受体相互作用蛋白激酶2下游原-IL-1β的成熟和分泌。我们为这些作用提供了分子基础，因为我们发现NOD2-S既与NOD2相互作用，又与受体相互作用蛋白激酶2相互作用，并通过干扰NOD2的寡聚而抑制结节组装。这些数据揭示了细胞内天然免疫调节的另一个复杂程度，并可能对理解NOD/NALP蛋白驱动的疾病病理生理有重要的分子意义。
Alterations in splicing patterns of genes contribute to the regulation of gene function by generating endogenous inhibitor or activator molecules. Nucleotide-binding and oligomerization domain (NOD) 2 is an intracellular receptor for bacterial cell wall components and plays an important role in initiating immune responses against cytoinvasive pathogens. NOD2 overexpression sensitizes intestinal epithelial cells toward bacterial cell wall components, activates the proinflammatory transcription factor NF-kappa B, and induces the subsequent release of the chemotactic cytokine IL-8. Here, we have assessed the regulation and function of a transcript isoform of NOD2, NOD2-S, generated by the skipping of the third exon, which encodes for a protein that is truncated within the second caspase recruitment (CARD) domain. NOD2-S is preferentially expressed in the human colon and is up-regulated by the antiinflammatory cytokine IL-10. Overexpression of NOD2-S down-regulates NOD2-induced NF-kappa B activation and IL-8 release. Moreover, NOD2-S also interferes with the maturation and secretion of pro-IL-1 beta downstream of NOD2 and its adaptor molecule receptor-interacting protein kinase 2. We provide a molecular basis for these effects, as we show that NOD2-S interacts with both, NOD2 and receptor-interacting protein kinase 2 and inhibits the "nodosome" assembly by interfering with the oligomerization of NOD2. These data unveil another level of complexicity in the regulation of intracellular innate immunity and may have important implications for the molecular understanding of NOD/NALP protein-driven disease pathophysiology.