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

Ting Wang (1) , Zheng Wang (2) , Lauriane de Fabritus (3) , Jinglian Tao (4) , Essa Saied (5) , Ho-Joon Lee (1) , Bulat Ramazanov (1) , Benjamin Jackson (4) , Daniel Burkhardt (1) , Mikhail Parker (4) , Anne Gleinich (4) , Zhirui Wang (4) , Dong Eun Seo (4) , Ting Zhou (1) , Shihao Xu (6) , Irina Alecu (7) , Parastoo Azadi (4) , Christoph Arenz (5) , Thorsten Hornemann (8) , Smita Krishnaswamy (1) , Serge van de Pavert (3) , Susan Kaech (6) , Natalia Ivanova (4) , Fabio Santori (1)

1 Yale University [New Haven]
2 QDU - Qingdao University
3 CIML - Centre d'Immunologie de Marseille - Luminy
4 University of Georgia [USA]
5 HU Berlin - Humboldt-Universität zu Berlin = Humboldt University of Berlin = Université Humboldt de Berlin
6 The Salk Institute for Biological Studies
7 uOttawa - Université d'Ottawa [Ontario]
8 UZH - Universität Zürich [Zürich] = University of Zurich

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.

Mots clés: NR2F1; NR2F2; COUP-TF; NR2F6; sphingolipid; 1-deoxysphingosine; cardiomyocyte; SPTLC2; metabolism; lymphatic

Domaines: Sciences du Vivant [q-bio]

Ting Wang, Zheng Wang, Lauriane de Fabritus, Jinglian Tao, Essa Saied, et al.. 1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development. Developmental Cell, 2021, 56 (22), pp.3128-3145.e15. ⟨10.1016/j.devcel.2021.10.018⟩. ⟨hal-03566022⟩