Abstract
Pattern recognition receptors (PRRs) are crucial for host defense and tissue homeostasis against infecting pathogens. PRRs are highly conserved cross species, suggesting their key roles in fundamental biological processes. Though much have been learned for NOD1 receptor in the innate and adaptive immune responses, the roles of NOD1 during embryonic and larval stages remain poorly understood. Here, we report that NOD1 is necessary for the modulation of PI3K-Akt pathway and larval survival in zebrafish. Transcriptome analysis revealed that the significantly enriched pathways in NOD1−/− zebrafish larvae were mainly involved in metabolism and immune system processes. Biochemical analysis demonstrated that NOD1 was required for the expression of CD44a that, in turn, activated the PI3K-Akt pathway during larval development. Conversely, over-expression of CD44a in NOD1-deficient zebrafish restored the modulation of the PI3K-Akt pathway and improved larval survival. Collectively, our work indicates that NOD1 plays a previously undetected protective role in larval survival through CD44a-mediated activation of the PI3K-Akt signaling.
Highlights
NOD-like receptors (NLRs) are a large family of intracellular pattern recognition receptors (PRRs) with a characteristic arrangement of nucleotide-binding domain (NBD) and leucine-rich repeat (LRR) regions
We demonstrate that zebrafish NOD1 is required for hatching process and larval survival
The present study demonstrates that NOD1 is a multifunctional regulator that drives the expression of multiple receptors and immune signaling pathways
Summary
NOD-like receptors (NLRs) are a large family of intracellular pattern recognition receptors (PRRs) with a characteristic arrangement of nucleotide-binding domain (NBD) and leucine-rich repeat (LRR) regions. NOD1 interacts with receptor-interacting protein 2 (RICK/RIP2) through CARD-CARD domain interaction, which triggers the activation of NF-κB and MAPK (mitogen-associated protein kinase) pathways[7, 8]. These signaling cascades potently up-regulate the production of pro-inflammatory cytokines and antimicrobial molecules, constituting the innate immune response. In addition to the crucial role of mediating T-cell extravasation[28, 29], regulating effector T-cell responses[30] and T-cell development[31], CD44 activates the PI3K-Akt pathway which is associated with cell survival in various cell types including www.nature.com/scientificreports/. Whether the functional correlation among NOD1, CD44 and PI3K-Akt pathway exists in the immune system, especially during early ontogenesis, is still unclear
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