多溴联苯醚诱导鞘氨醇菌形成“鞘脂变阻器”的信号转导过程及响应蛋白的作用机制

To date, little is known about the physiological roles of glycosphingolipids (GSLs) and their metabolites in Sphingomonas spp. However, the level of GSLs metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate, which have been called the “sphingolipid rheostat” in eukaryotic cells, plays an important role in signal transduction and immune receptor recognition. Moreover, polybrominated diphenyl ethers (PBDEs) are found to exhibit interference on the signal transduction pathways of nerve cells with high content of GSLs. In our previous study, the change of cell surface hydrophobicity (CSH), the decomposition of GSLs, and simultaneous the formation of outer membrane proteins (OMPs) by Sphingobium sp. C1 was observed under the condition of PBDEs exposure. It was hypothesized that the decomposition of GSLs mediated the signal transduction of PBDEs biotoxicity and resulted in the membrane transportation of PBDEs by the newly formed OMPs.. In order to confirm the hypothesis mentioned above, “sphingolipid rheostat” signal transduction and membrane transportation of PBDEs by Sphingobium sp. C1 will be studied under the condition of PBDEs exposure in this project. Three scientific contents will be involved in this project about CSH, structural composition of OMPs and structural decomposition of GSLs; signal transduction by the “sphingolipid rheostat”; and PBDEs transportation by the newly formed OMPs. It is expected to find new mechanisms of signal transduction of PBDEs biotoxicity and membrane transportation of PBDEs. It will provide a reference for the removal of PBDEs biotoxicity and even for the treatment of disease induced by PBDEs.

鞘糖脂及其代谢物在鞘氨醇菌中的生理作用尚不明确，但在动物细胞中却可以形成“鞘脂变阻器”，作为信号分子参与信号通路调节。而多溴联苯醚对鞘糖脂含量高的动物神经细胞具有信号转导的干扰作用。项目前期研究发现鞘氨醇菌C1可耐受高浓度多溴联苯醚，过程伴随外膜鞘糖脂的分解代谢以及外膜通道蛋白的新合成。推测多溴联苯醚诱导鞘糖脂分解产生具有毒性效应信号转导作用的代谢物，继而激活细胞膜产生可调节多溴联苯醚分配的转运通道蛋白。.针对上述假说，项目以特异含有鞘糖脂的高耐受芳烃的鞘氨醇菌C1为对象，从细胞表面性质与鞘糖脂代谢及外膜通道蛋白合成相关性、“鞘脂变阻器”信号转导过程、外膜通道蛋白转运作用三方面，开展多溴联苯醚诱导鞘氨醇菌形成“鞘脂变阻器”的信号转导过程及响应蛋白的作用机制研究，以期揭示多溴联苯醚毒性效应的信号转导机制以及微生物耐毒性机制，为解除多溴联苯醚生物毒性效应甚至治疗多溴联苯醚诱发疾病提供一些参考。

鞘糖脂及其代谢物在鞘氨醇菌中的生理作用尚不明确，但在动物细胞中却可以形成“鞘脂变阻器”，作为信号分子参与信号通路调节。项目针对一株高细胞表面疏水性的鞘氨醇菌Sphingobium hydrophobicum C1耐受多溴联苯醚毒性过程伴随鞘糖脂分解和外膜蛋白合成的现象，从细胞表面性质与鞘糖脂代谢及外膜通道蛋白合成相关性、多溴联苯醚毒性信号转导过程以及外膜通道蛋白转运作用三个方面，开展多溴联苯醚诱导鞘氨醇菌形成“鞘脂变阻器”的信号转导过程及响应蛋白的作用机制研究。. 研究结果表明，多溴联苯醚通过疏水相互作用吸附到高细胞表面疏水性的鞘氨醇菌S. hydrophobicum C1的细胞膜上，引起菌体细胞膜通透性改变和细胞表面疏水性增加。多溴联苯醚被位于细胞外膜上Chr1_2466基因编码的具有Cache结构域的受体蛋白所特异识别，并进一步诱导该组氨酸激酶类受体蛋白的上调表达，引起细胞膜鞘糖脂分解产生鞘氨醇传递下游信号，继而激活Chr1_2500基因编码的具有多个β折叠片相互作用形成中空疏水内腔的细胞膜转运通道蛋白的合成。该转运通道蛋白可以调节多溴联苯醚转运通过细胞膜，并分配到细胞质中进行降解，从而有效解除多溴联苯醚对疏水鞘氨醇菌S. hydrophobicum C1的毒性效应。. 项目研究发现了多溴联苯醚的特异胞外识别受体蛋白以及跨膜转运通道蛋白，揭示了多溴联苯醚毒性效应的信号转导机制以及疏水鞘氨醇菌S. hydrophobicum C1的耐毒性机制。这为解除多溴联苯醚生物毒性效应甚至治疗多溴联苯醚诱发疾病提供了一些理论参考。