Abstract
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 Caenorhabditis elegans, the spin-2 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 spin-2 and three additional genes in the C. elegans 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 C. elegans immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene (sphk-1) or in the S1P transporter genes spin-2 or spin-3 decreased nematode survival after infection with Pseudomonas aeruginosa or Enterococcus faecalis. In contrast to spin-2 and spin-3, mutating spin-1 leads to an increase in resistance to P. aeruginosa. Consistent with these results, when wild-type C. elegans were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with P. aeruginosa and E. faecalis. In comparison, spin-2 and spin-3 mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the spin-1 mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward P. aeruginosa and Escherichia coli and only minimal activity against E. faecalis MMH594 (40 µM). These data suggest that spin-2 and spin-3, on the one hand, and spin-1, on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in C. elegans sek-1 and pmk-1 mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.
Highlights
Studies investigating the response of Caenorhabditis elegans to different pathogens, including bacteria and fungi, have revealed that conserved signaling pathways, such as the p38 mitogen-activated protein kinase (p38 MAPK) pathway and conserved transcription factors such as hlh-30 (Helix Loop Helix-30, MITF/TFEB), play important roles in C. elegans immune responses [1,2]
It was previously shown that spin-2 is upregulated in C. elegans infected with Serratia marcescens [23] or Enterococcus faecalis [5]
Tested the role of S1P transporters during infection using deletion mutant animals made by the C. elegans Deletion Mutant Consortium [24]
Summary
Studies investigating the response of Caenorhabditis elegans to different pathogens, including bacteria and fungi, have revealed that conserved signaling pathways, such as the p38 mitogen-activated protein kinase (p38 MAPK) pathway and conserved transcription factors such as hlh-30 (Helix Loop Helix-30, MITF/TFEB), play important roles in C. elegans immune responses [1,2]. These studies have identified a variety of potential target genes that may play critical roles in the response to infection Genes activated by both Gram-negative and Gram-positive bacteria are of interest for understanding general immune responses of the host to infection and may be potential therapeutic targets for new broad-spectrum antimicrobials. An example of such a broadly activated immune-regulated C. elegans gene is SPINSTER-2 abbreviated as spin-2 [3,5], which encodes a sphingosine-1-phosphate (S1P) transporter. We hypothesized that sphk-1 and the 4 S1P transporters encoding genes spin-1, -2, -3, and -4 may play an important role in the C. elegans immune response. We demonstrate that deletion mutants of sphk-1, spin-1, spin-2, and spin-3 exhibit aberrant immune responses in which exogenous S1P increases C. elegans resistance to P. aeruginosa and E. faecalis, and the immune modulatory activity of S1P is partially dependent on the p38 MAPK signaling pathway and the transcription factor hlh-30
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
