1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.

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. [Display omitted] • 1-deoxyphingosines bind and modulate NR2F1 and NR2F2 transcriptional activity • Genetic deletion of Sptlc2 phenocopies Nr2f2 deficiency in lymphatic development • Inhibition of sphingolipid synthesis impairs human cardiomyocyte differentiation • 1-deoxysphingosine supplementation promotes human cardiomyocyte maturation Wang et al. identify 1-deoxysphingosines as modulators of COUP-TF activity. Inhibition of sphingolipid biosynthesis mimics COUP-TF knockout phenotypes in lymphatic development and in human ESC-derived cardiomyocytes, whereas elevated levels of 1-deoxysphingosines enhance cardiomyocyte differentiation. Thus, sphingolipids could be physiological ligands for COUP-TFs and could play a critical role in development. [ABSTRACT FROM AUTHOR]