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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.
Figure 1. Identification and characterization of the miR-31 binding sites in the 3’-untranslated region (3’-UTR) of AjCTRP9. (A) Schematic representation of putative miR-31 binding sites in the AjCTRP9 3’-UTR and the mutant sites (the protein domain of AjCTRP9 was annotated with SMART at http://smart.embl.de/), the red letters represent “seed†regions. (B)
AjCTRP9 luciferase reporter assays conducted in HEK-293T cells carrying the wild-type AjCTRP9 3’-UTR and a mutant AjCTRP9 3’-UTR (final concentration: 100 nM).
Figure 5. Principal component analysis score scatter plot in ESI+ (A) and ESI− (B) mode for the total lipids of Apostichopus japonicus between the siAjCTRP9 group (green) and the negative control group (blue).
Figure 6. Scatter plot of OPLS-DA scores (A,C) and validation plot (B,D) of the PLS-DA analysis on siAjCTRP9 group in both positive (A,B) and negative (C,D) ion scan modes compared with the negative control group.
Figure 7. OPLS loading S-plot for the total lipids of the siAjCTRP9 group and the negative control group detected in the ESI+ (A) and ESI− (B) modes. Significant ions are outlined in red and listed in Table 1.
Figure 11. Schematic representation of the involvement of miR-31 in disturbing the lipid metabolism balance by targeting AjCTRP9.
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