| Literature DB >> 34762852 |
Ting Wang1, Zheng Wang2, Lauriane de Fabritus3, Jinglian Tao4, Essa M Saied5, Ho-Joon Lee6, Bulat R Ramazanov7, Benjamin Jackson8, Daniel Burkhardt9, Mikhail Parker8, Anne S Gleinich10, Zhirui Wang10, Dong Eun Seo8, Ting Zhou11, Shihao Xu12, Irina Alecu13, Parastoo Azadi10, Christoph Arenz14, Thorsten Hornemann15, Smita Krishnaswamy9, Serge A van de Pavert3, Susan M Kaech16, Natalia B Ivanova17, Fabio R Santori18.
Abstract
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.Entities:
Keywords: 1-deoxysphingosine; COUP-TF; NR2F1; NR2F2; NR2F6; SPTLC2; cardiomyocyte; lymphatic; metabolism; sphingolipid
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Year: 2021 PMID： 34762852 PMCID： PMC8628544 DOI： 10.1016/j.devcel.2021.10.018
Source DB: PubMed Journal: Dev Cell ISSN： 1534-5807 Impact factor: 12.270