RIP2 Is a Critical Regulator for NLRs Signaling and MHC Antigen Presentation but Not for MAPK and PI3K/Akt Pathways

Abstract

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 in vitro. Very little is known about the role and mechanisms of piscine NOD-RIP2 axis in vivo. 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.

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

“…S2). Both genes have NOD-like receptor (NLR) domains that possess NACHT (NTPase) and leucine-rich repeat (LRR) protein domains, important for innate immune system antigen interactions [36]. To validate the RNA-seq dataset, quantitative real-time PCR (qRT-PCR) was performed on mineralised tissue growth and degradation markers and showed concordant data between RNA-seq and qRT-PCR assays of all selected amplicons (Fig.…”

CD44a functions as a regulator of p53 signaling, apoptosis and autophagy in the antibacterial immune response

“…NOD1 is the best-characterized antibacterial pattern recognition receptor (PRR). Our previous studies have revealed that both NOD1 and its adapter protein RIPK2 influence the expression of CD44a enormously, but not for CD44c 19 – 21 . Furthermore, NOD1 plays a protective role in larval survival through CD44a-mediated PI3K-Akt signaling 20 .…”

Inflammasomes and Type 1 Diabetes

“…These findings were also supported by other studies in NOD mice, demonstrating that NOD2-deficient NOD mice were protected from type 1 diabetes development, and this was dependent on the gut microbiota composition ( 127 ), whereas RIP2-deficient NOD mice were not protected ( 120 ). Interestingly, both NOD1 and NOD2 appear to have RIP2 independent functions; NOD2 binds CARD9 to mediate downstream signaling independent of RIP2 ( 128 ), while NOD1 regulates MAPK signaling independent of RIP2 ( 129 ). It is still unclear what the role, if any, NOD1 has in the immunopathogenesis of autoimmune Type 1 diabetes.…”