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

Area of Science:

• Biochemistry
• Molecular Biology
• Developmental Biology

Background:

• Nuclear hormone receptors (NHRs) regulate critical physiological processes.
• Understanding NHR modulators is key to linking metabolism and gene networks.
• Orphan NHRs NR2F1/2 are vital for nervous system, heart, and vascular development.

Purpose of the Study:

• To identify physiological modulators of nuclear hormone receptor activity.
• To investigate the role of sphingolipids in regulating NR2F1/2 function.
• To explore the connection between sphingolipid metabolism and developmental gene programs.

Main Methods:

• Screening metabolic enzyme libraries with substrates and products.
• Utilizing cell-based assays to test modulation of NR2F1/2 transcriptional activity.
• Employing genetic and pharmacological inhibition of sphingolipid biosynthesis.

Main Results:

• 1-deoxysphingosines identified as modulators of NR2F1 and NR2F2 (COUP-TFs).
• Non-canonical sphingolipids bind to NR2F1/2 ligand-binding domains and alter activity.
• Inhibition of sphingolipid synthesis mimics NR2F1/2 deficiency phenotypes.
• Elevated 1-deoxysphingosine levels activate NR2F1/2-dependent differentiation.

Conclusions:

• 1-deoxysphingosines are physiological regulators of NR2F1/2-mediated transcription.
• This study uncovers a novel mechanism linking sphingolipid metabolism to NHR signaling.
• Findings provide insights into developmental processes regulated by NR2F1/2.