NOD1/2 Signaling Pathway

NOD1 is ubiquitously expressed, while NOD2 expression is restricted to monocytes, macrophages, dendritic cells, and intestinal Paneth cells (Inohara et al. 2005). NOD1 and NOD2 activation induces transcription of immune response genes, predominantly mediated by the proinflammatory transcriptional factor NFkappaB but also by AP-1 and Elk-1 (Inohara et al. 2005). NFkappaB translocates to the nucleus following release from IkappaB proteins. NOD1 and NOD2 signaling involves an interaction between their caspase-recruitment domain (CARD) and the CARD of the kinase RIPK2 (RIP2/RICK). This leads to the activation of the NFkappaB pathway and MAPK pathways (Windheim et al. 2007).<br>Activated NODs oligomerize via their NACHT domains, inducing physical proximity of RIP2 proteins that is believed to trigger their K63-linked polyubiquitination, facilitating recruitment of the TAK1 complex. RIP2 also recruits NEMO, bringing the TAK1 and IKK complexes into proximity, leading to NF-kappaB activation and activation of MAPK signaling. Recent studies have demonstrated that K63-linked regulatory ubiquitination of RIP2 is essential for the recruitment of TAK1 (Hasegawa et al. 2008, Hitosumatsu et al. 2008). As observed for toll-like receptor (TLR) signaling, ubiquitination can be removed by the deubiquitinating enzyme A20, thereby dampening NOD1/NOD2-induced NF-kappaB activation. NOD1 and NOD2 both induce K63-linked ubiquitination of RIP2, but NOD2-signaling appears to preferentially utilize the E3 ligase TRAF6, while TRAF2 and TRAF5 were shown to be important for NOD1-mediated signaling. In both cases, activation of NF-kappaB results in the upregulated transcription and production of inflammatory mediators.

NOD1在体内广泛表达，而NOD2的表达则局限于单核细胞、巨噬细胞、树突状细胞以及肠道的潘内特细胞（Inohara等人，2005年）。NOD1与NOD2的激活可诱导免疫反应基因的转录，其主要通过促炎转录因子NFκB介导，亦可通过AP-1和Elk-1实现（Inohara等人，2005年）。NFκB在IkappaB蛋白释放后转移至细胞核。NOD1与NOD2的信号转导涉及它们各自的caspase募集结构域（CARD）与激酶RIPK2（RIP2/RICK）的CARD之间的相互作用，进而激活NFκB途径和MAPK途径（Windheim等人，2007年）。激活的NODs通过其NACHT结构域发生寡聚化，引发RIP2蛋白的物理接近，据信这触发了其K63连接的多泛素化，从而促进了TAK1复合物的募集。RIP2还募集NEMO，使TAK1和IKK复合物相互靠近，导致NF-kappaB的激活和MAPK信号通路的激活。近期研究表明，K63连接的RIP2调节性泛素化对于TAK1的募集至关重要（Hasegawa等人，2008年，Hitosumatsu等人，2008年）。如同toll样受体（TLR）信号转导所见，泛素化可通过去泛素化酶A20移除，从而减弱NOD1/NOD2诱导的NF-kappaB激活。NOD1和NOD2均诱导RIP2的K63连接泛素化，但NOD2信号转导似乎优先利用E3连接酶TRAF6，而TRAF2和TRAF5已被证实对于NOD1介导的信号转导至关重要。在两种情况下，NF-kappaB的激活均导致炎症介质的转录和生产的上调。