Department of Immunobiology, Yale University, New Haven, CT 06520, USA; Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, Shandong 266071, China; Department of Reproductive Medicine, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China.
Aix-Marseille Universite, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille Cedex 9, France.
Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China; Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA.
Institut für Chemie, Humboldt Universität zu Berlin, Berlin 12489, Germany; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
Department of Genetics, Yale University, New Haven, CT 06520, USA; Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
Department of Cell Biology, Yale University, New Haven, CT 06520, USA.
Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA.
Department of Genetics, Yale University, New Haven, CT 06520, USA.
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
NOMIS Center for Immunobiology and Microbial Pathogenesis, the Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada.
Institut für Chemie, Humboldt Universität zu Berlin, Berlin 12489, Germany.
Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich 8091, Switzerland.
NOMIS Center for Immunobiology and Microbial Pathogenesis, the Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: skaech@salk.edu.
Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA. Electronic address: natalia.ivanova@uga.edu.
Department of Immunobiology, Yale University, New Haven, CT 06520, USA. Electronic address: fabio.santori@yale.edu.
Identification of physiological modulators of nuclear hormone receptor (NHR) activity is paramount for understanding the link between metabolism and transcriptional networks that orchestrate development and cellular physiology. Using libraries of metabolic enzymes alongside their substrates and products, we identify 1-deoxysphingosines as modulators of the activity of NR2F1 and 2 (COUP-TFs), which are orphan NHRs that are critical for development of the nervous system, heart, veins, and lymphatic vessels. We show that these non-canonical alanine-based sphingolipids bind to the NR2F1/2 ligand-binding domains (LBDs) and modulate their transcriptional activity in cell-based assays at physiological concentrations. Furthermore, inhibition of sphingolipid biosynthesis phenocopies NR2F1/2 deficiency in endothelium and cardiomyocytes, and increases in 1-deoxysphingosine levels activate NR2F1/2-dependent differentiation programs. Our findings suggest that 1-deoxysphingosines are physiological regulators of NR2F1/2-mediated transcription.
