State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Immunol. 2018 Apr 10;9:726. doi: 10.3389/fimmu.2018.00726. eCollection 2018.
RIP2 is an adaptor protein which is essential for the activation of NF-κB and NOD1- and NOD2-dependent signaling. Although NOD-RIP2 axis conservatively existed in the teleost, the function of RIP2 was only reported in zebrafish, goldfish, and rainbow trout . Very little is known about the role and mechanisms of piscine NOD-RIP2 axis . Our previous study showed the protective role of zebrafish NOD1 in larval survival through CD44a-mediated activation of PI3K-Akt signaling. In this study, we examined whether RIP2 was required for larval survival with or without pathogen infection, and determined the signaling pathways modulated by RIP2. Based on our previous report and the present study, our data demonstrated that NOD1-RIP2 axis was important for larval survival in the early ontogenesis. Similar to NOD1, RIP2 deficiency significantly affected immune system processes. The significantly enriched pathways were mainly involved in immune system, such as "Antigen processing and presentation" and "NOD-like receptor signaling pathway" and so on. Furthermore, both transcriptome analysis and qRT-PCR revealed that RIP2 was a critical regulator for expression of NLRs (NOD-like receptors) and those genes involved in MHC antigen presentation. Different from NOD1, the present study showed that NOD1, but not RIP2 deficiency significantly impaired protein levels of MAPK pathways. Although RIP2 deficiency also significantly impaired the expression of CD44a, the downstream signaling of CD44a-Lck-PI3K-Akt pathway remained unchanged. Collectively, our works highlight the similarity and discrepancy of NOD1 and RIP2 in the regulation of immune signaling pathways in the zebrafish early ontogenesis, and confirm the crucial role of RIP2 in NLRs signaling and MHC antigen presentation, but not for MAPK and PI3K/Akt pathways.
RIP2 是一种衔接蛋白，对于 NF-κB 和 NOD1-和 NOD2-依赖性信号的激活至关重要。尽管 NOD-RIP2 轴在硬骨鱼中保守存在，但 RIP2 的功能仅在斑马鱼、金鱼和虹鳟鱼中报道过。关于鱼类 NOD-RIP2 轴的作用和机制知之甚少。我们之前的研究表明，斑马鱼 NOD1 通过 CD44a 介导的 PI3K-Akt 信号的激活在幼虫存活中发挥保护作用。在这项研究中，我们研究了 RIP2 是否需要在有无病原体感染的情况下维持幼虫存活，并确定了 RIP2 调节的信号通路。基于我们之前的报告和本研究，我们的数据表明 NOD1-RIP2 轴对于早期胚胎发生中的幼虫存活很重要。与 NOD1 相似，RIP2 缺陷显著影响免疫系统过程。显著富集的途径主要涉及免疫系统，如“抗原加工和呈递”和“NOD 样受体信号通路”等。此外，转录组分析和 qRT-PCR 显示，RIP2 是 NLRs（NOD 样受体）和那些参与 MHC 抗原呈递的基因表达的关键调节剂。与 NOD1 不同，本研究表明，NOD1 而不是 RIP2 缺陷显著降低了 MAPK 途径的蛋白水平。尽管 RIP2 缺陷也显著降低了 CD44a 的表达，但 CD44a-Lck-PI3K-Akt 途径的下游信号仍然不变。总的来说，我们的工作强调了 NOD1 和 RIP2 在斑马鱼早期胚胎发生中免疫信号通路调节中的相似性和差异，并证实了 RIP2 在 NLRs 信号和 MHC 抗原呈递中的关键作用，但对 MAPK 和 PI3K/Akt 途径没有作用。
