Institute of Clinical Molecular Biology, Christian Albrechts University, D-24105 Kiel, Germany.
Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21426-31. doi: 10.1073/pnas.1209673109. Epub 2012 Dec 3.
The intracellular nucleotide-binding oligomerization domain-2 (NOD2) receptor detects bacteria-derived muramyl dipeptide (MDP) and activates the transcription factor NF-κB. Here we describe the regulatome of NOD2 signaling using a systematic RNAi screen. Using three consecutive screens, we identified a set of 20 positive NF-κB regulators including the known pathway members RIPK2, RELA, and BIRC4 (XIAP) as well as FRMPD2 (FERM and PDZ domain-containing 2). FRMPD2 interacts with NOD2 via leucine-rich repeats and forms a complex with the membrane-associated protein ERBB2IP. We demonstrate that FRMPD2 spatially assembles the NOD2-signaling complex, hereby restricting NOD2-mediated immune responses to the basolateral compartment of polarized intestinal epithelial cells. We show that genetic truncation of the NOD2 leucine-rich repeat domain, which is associated with Crohn disease, impairs the interaction with FRMPD2, and that intestinal inflammation leads to down-regulation of FRMPD2. These results suggest a structural mechanism for how polarity of epithelial cells acts on intestinal NOD-like receptor signaling to mediate spatial specificity of bacterial recognition and control of immune responses.
细胞内核苷酸结合寡聚化结构域 2（NOD2）受体可识别细菌来源的 muramyl dipeptide（MDP）并激活转录因子 NF-κB。在此，我们使用系统 RNAi 筛选来描述 NOD2 信号的调节组。通过连续三次筛选，我们鉴定出了一组 20 个阳性 NF-κB 调节剂，包括已知的通路成员 RIPK2、RELA 和 BIRC4（XIAP）以及 FRMPD2（FERM 和 PDZ 结构域蛋白 2）。FRMPD2 通过富含亮氨酸重复序列与 NOD2 相互作用，并与膜相关蛋白 ERBB2IP 形成复合物。我们证明 FRMPD2 空间组装 NOD2 信号复合物，从而将 NOD2 介导的免疫反应限制在极化肠上皮细胞的基底外侧隔室。我们表明，与克罗恩病相关的 NOD2 富含亮氨酸重复结构域的遗传截断会损害与 FRMPD2 的相互作用，并且肠道炎症会导致 FRMPD2 的下调。这些结果表明了上皮细胞极性如何对肠道 NOD 样受体信号起作用以介导细菌识别的空间特异性和免疫反应的控制的结构机制。
