Abstract
Invertebrates rely on innate immunity, including humoral and cellular immunity, to resist pathogenic infection. Previous studies showed that forkhead box transcription factor O (FOXO) participates in mucosal immune responses of mammals and the gut humoral immune regulation of invertebrates. However, whether FOXO is involved in systemic and cellular immunity regulation in invertebrates remains unknown. In the present study, we identified a FOXO from shrimp (Marsupenaeus japonicus) and found that it was expressed at relatively basal levels in normal shrimp, but was upregulated significantly in shrimp challenged by Vibrio anguillarum. FOXO played a critical role in maintaining hemolymph and intestinal microbiota homeostasis by promoting the expression of Relish, the transcription factor of the immune deficiency (IMD) pathway for expression of antimicrobial peptides (AMPs) in shrimp. We also found that pathogen infection activated FOXO and induced its nuclear translocation by reducing serine/threonine kinase AKT activity. In the nucleus, activated FOXO directly regulated the expression of its target Amp and Relish genes against bacterial infection. Furthermore, FOXO was identified as being involved in cellular immunity by promoting the phagocytosis of hemocytes through upregulating the expression of the phagocytotic receptor scavenger receptor C (Src), and two small GTPases, Rab5 and Rab7, which are related to phagosome trafficking to the lysosome in the cytoplasm. Taken together, our results indicated that FOXO exerts its effects on homeostasis of hemolymph and the enteric microbiota by activating the IMD pathway in normal shrimp, and directly or indirectly promoting AMP expression and enhancing phagocytosis of hemocytes against pathogens in bacteria-infected shrimp. This study revealed the different functions of FOXO in the mucosal (local) and systemic antibacterial immunity of invertebrates.
Highlights
The forkhead box transcription factor O family proteins (FOXOs) are involved in various critical biological process of organisms, including cell cycle regulation, repair of damaged DNA, anti-cancer immunity, and life span regulation [1,2]
We identified a FOXO from kuruma shrimp (Marsupenaeus japonicus) and found that it played a critical role in maintaining hemolymph and intestinal microbiota homeostasis by promoting the expression of Relish, the transcription factor of immune deficiency (IMD) pathway for expression of antimicrobial peptides (AMPs) in shrimp
We found that pathogen infection activated FOXO and induced its nuclear translocation by reducing serine/threonine kinase AKT activity and directly regulated the expression of its target Amp and Relish genes against bacterial infection
Summary
The forkhead box transcription factor O family proteins (FOXOs) are involved in various critical biological process of organisms, including cell cycle regulation, repair of damaged DNA, anti-cancer immunity, and life span regulation [1,2]. The transcriptional activity of FOXO is regulated by several kinds of post-translational modifications, such as phosphorylation, acetylation, methylation, and ubiquitination [4]. These modifications affect FOXO nuclear translocation or exit from the nucleus, and its interaction with co-repressors and coactivators, which can promote or decrease FOXO activity and mediate its different biological functions [5,6]. FOXOs are activated by various extracellular stimuli, including growth factors, cytokines, and hormones [8] Growth signals, such as insulin or insulin-like growth factor 1 (IGF-1), interact with receptors of the insulin pathway, and activate phosphatidylinositol 3-kinase (PI3K) signaling, leading to phosphorylation of FOXO by the serine/threonine kinase, protein kinase B (AKT) [9].
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