Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.
Int J Mol Sci. 2020 Oct 22;21(21):7813. doi: 10.3390/ijms21217813.
Sphingosine-1-phophate (S1P) is a sphingolipid-derived signaling molecule that controls diverse cellular functions including cell growth, homeostasis, and stress responses. In a variety of metazoans, cytosolic S1P is transported into the extracellular space where it activates S1P receptors in a concentration-dependent manner. In the free-living nematode , the gene, which encodes a S1P transporter, is activated during Gram-positive or Gram-negative bacterial infection of the intestine. However, the role during infection of and three additional genes in the genome encoding other putative S1P transporters has not been elucidated. Here, we report an evolutionally conserved function for S1P and a non-canonical role for S1P transporters in the immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene () or in the S1P transporter genes or decreased nematode survival after infection with or . In contrast to and , mutating leads to an increase in resistance to . Consistent with these results, when wild-type were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with and . In comparison, and mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward and and only minimal activity against MMH594 (40 µM). These data suggest that and , on the one hand, and , on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in and mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.
鞘氨醇-1-磷酸（S1P）是一种鞘脂衍生的信号分子，控制着包括细胞生长、稳态和应激反应在内的多种细胞功能。在各种后生动物中，细胞质中的 S1P 被转运到细胞外空间，在那里以浓度依赖的方式激活 S1P 受体。在自由生活的线虫中，编码 S1P 转运蛋白的 基因在肠道中被革兰氏阳性或革兰氏阴性细菌感染时被激活。然而，在感染过程中， 基因以及基因组中另外三个编码其他假定 S1P 转运蛋白的基因的作用尚未阐明。在这里，我们报告了 S1P 在 免疫反应中对细菌病原体的保守功能和 S1P 转运蛋白的非经典作用。我们发现，鞘氨醇激酶基因 () 或 S1P 转运蛋白基因 或 的突变降低了线虫在感染 或 后的存活率。与 和 不同， 的突变导致对 的抗性增加。与这些结果一致的是，当用细胞外 S1P 补充野生型 时，我们发现当用 和 挑战时，它们的寿命延长。相比之下， 和 突变抑制了 S1P 拯救线虫免受病原体介导的杀伤的能力，而 突变对 S1P 的免疫增强活性没有影响。S1P 对 和 没有抗菌活性，对 MMH594（40 µM）只有轻微的活性。这些数据表明，一方面 和 ，另一方面 和 ，将 S1P 跨细胞膜向相反方向转运。最后，S1P 的免疫调节作用在 和 突变体中减弱，表明 S1P 的免疫调节作用是通过 p38 MAPK 信号通路介导的。
