Abstract
The biological functions of microRNAs (miRNAs) have been studied in a number of eukaryotic species. Recent studies on vertebrate animals have demonstrated critical roles of miRNA in immune and metabolic activities. However, studies on the functions of miRNA in invertebrates are very limited. Here, we demonstrated that miR-31 from Apostichopus japonicus disrupts the balance of lipid metabolism, thus resulting in cell apoptosis by targeting complement C1q tumor necrosis factor-related protein 9 (AjCTRP9), a novel adipokine with pleiotropic functions in immunity and metabolism. Lipidomic analysis suggested that the intercellular lipid metabolites were markedly altered, and three ceramide (Cer) species synchronously increased in the AjCTRP9-silenced coelomocytes. Moreover, exogenous Cer exposure significantly induced apoptosis in the coelomocytes in vivo, in agreement with findings from miR-31 mimic- or AjCTRP9 small-interfering RNA-transfected coelomocytes. Furthermore, we found that the imbalance in sphingolipid metabolism triggered by the overproduction of Cers ultimately resulted in the activation of the apoptosis initiator caspase-8 and executioner caspase-3. Our findings provide the first direct evidence that miR-31 negatively modulates the expression of AjCTRP9 and disturbance of Cer channels, thus leading to caspase-3- and caspase-8-dependent apoptosis, during the interactions between pathogens and host.
Highlights
After the invasion of pathogens, the innate immune response reacts immediately as the first barrier to defend the host
Our results clearly demonstrated that miR-31, a multifunctional regulatory molecule, negatively modulates the expression of AjCTRP9 and induces cell apoptosis by disturbing the lipid metabolism balance, resulting in the overproduction of Cers
A given miRNA may have multiple mRNA targets that are involved in nearly every biological process [54]. miR-31 belongs to a highly evolutionarily conserved miRNA “seed family” that participates in the immune response, and whose abnormal expression or function in the immune system has been linked to multiple diseases [55,56,57]
Summary
After the invasion of pathogens, the innate immune response reacts immediately as the first barrier to defend the host. Various cellular and humoral defense pathways are simultaneously activated through different signaling networks. Efforts have been made to identify the roles of immune-related molecules during immune responses. Studies on the regulatory networks of these molecules and their interactions in host defense processes are lacking. Emerging studies deciphering the various cellular and signaling networks linking the immune defense with metabolism have contributed to the understanding of disease pathogenesis and the development of therapeutic strategies [1]. It is no surprise that the dissection of the interface connecting the immune system to metabolic pathways including glycolysis, lipid, and amino acid metabolism has recently gained interest [2, 3]
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