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.
Highlights
The receptor-interacting proteins (RIPs) are closely related to members of the interleukin-1-receptor-associated kinase (IRAK) family, and belong to a family of serine/threonine kinases
We reported that NOD1 deficiency affected immune system processes including “Antigen processing and presentation” and “NOD-like receptor signaling pathway,” and that NOD1 was essential for CD44a-mediated activation of the PI3K-Akt pathway and zebrafish larval survival [30]
A later report showed that TLR signaling was intact in cells from RIP2-deficient mice, but RIP2 deficiency leads to abrogation of signaling in response to stimulation of NOD1 and NOD2 by their specific ligands or the intracellular pathogen Listeria monocytogenes [37], which indicated that RIP2 mediated NOD signaling, but not TLR signal transduction
Summary
The receptor-interacting proteins (RIPs) are closely related to members of the interleukin-1-receptor-associated kinase (IRAK) family, and belong to a family of serine/threonine kinases. Seven different RIPs with each containing a homologous kinase domain (KD) have been described. RIP4 and RIP5 are characterized by the ankyrin repeats in their C-terminus [1, 2]. RIP6 and RIP7 are less related in structure to the other members and contain a number of additional and diverse domain structures, such as leucine-rich repeat regions, Ras of complex proteins (Roc), and C-terminal of Roc (COR) in their N-terminus [2, 3].
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