Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase

Hsueh Chun Wang, Tzu Hsuan Wong, Li Ting Wang, Hsiang Han Su, Hsiu Yueh Yu, Ai Hsuan Wu, Yu Chun Lin, Hua Ling Chen, Jau Ling Suen, Shih Hsien Hsu, Li Chen Chen, Yufeng Zhou, Shau Ku Huang

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Aryl hydrocarbon receptor (AhR), a cellular chemical sensor, controls cellular homeostasis, and sphingosine-1-phosphate (S1P), a bioactive intermediate of sphingolipid metabolism, is believed to have a role in immunity and inflammation, but their potential crosstalk is currently unknown. We aimed to determine whether there is a functional linkage between AhR signaling and sphingolipid metabolism. We showed that AhR ligands, including an environmental polycyclic aromatic hydrocarbon (PAH), induced S1P generation, and inhibited S1P lyase (S1PL) activity in resting cells, antigen/IgE-activated mast cells, and mouse lungs exposed to the AhR ligand alone or in combination with antigen challenge. The reduction of S1PL activity was due to AhR-mediated oxidation of S1PL at residue 317, which was reversible by the addition of an antioxidant or in cells with knockdown of the ORMDL3 gene encoding an ER transmembrane protein, whereas C317A S1PL mutant-transfected cells were resistant to the AhR-mediated effect. Furthermore, analysis of AhR ligand-treated cells showed a time-dependent increase of the ORMDL3–S1PL complex, which was confirmed by FRET analysis. This change increased the S1P levels, which in turn, induced mast cell degranulation via S1PR2 signaling. In addition, elevated levels of plasma S1P were found in children with asthma compared to non-asthmatic subjects. These results suggest a new regulatory pathway whereby the AhR–ligand axis induces ORMDL3-dependent S1P generation by inhibiting S1PL, which may contribute to the expression of allergic diseases.

Original languageEnglish
Pages (from-to)1-8
Number of pages8
JournalCellular and Molecular Immunology
DOIs
Publication statusAccepted/In press - Mar 23 2018
Externally publishedYes

Keywords

  • Aryl hydrocarbon receptor
  • ORMDL sphingolipid biosynthesis regulator 3
  • Sphingosine-1-phosphate
  • Sphingosine-1-phosphate lyase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase'. Together they form a unique fingerprint.

  • Cite this

    Wang, H. C., Wong, T. H., Wang, L. T., Su, H. H., Yu, H. Y., Wu, A. H., Lin, Y. C., Chen, H. L., Suen, J. L., Hsu, S. H., Chen, L. C., Zhou, Y., & Huang, S. K. (Accepted/In press). Aryl hydrocarbon receptor signaling promotes ORMDL3-dependent generation of sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cellular and Molecular Immunology, 1-8. https://doi.org/10.1038/s41423-018-0022-2