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

Published in: Developmental Cell, 2021, 56 (22), pp.3128-3145.e15. ⟨10.1016/j.devcel.2021.10.018⟩

Authors: Ting Wang, Zheng Wang, Lauriane de Fabritus, Jinglian Tao, Essa Saied, Ho-Joon Lee, Bulat Ramazanov, Benjamin Jackson, Daniel Burkhardt, Mikhail Parker, Anne Gleinich, Zhirui Wang, Dong Eun Seo, Ting Zhou, Shihao Xu, Irina Alecu, Parastoo Azadi, Christoph Arenz, Thorsten Hornemann, Smita Krishnaswamy, Serge van de Pavert, Susan Kaech, Natalia Ivanova, Fabio Santori

Summary

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.

Link to HAL – amu-03669075

Link to DOI – 10.1016/j.devcel.2021.10.018