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

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

doi:10.1016/j.devcel.2021.10.018

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

Dev Cell. 2021 Nov 22;56(22):3128-3145.e15. doi: 10.1016/j.devcel.2021.10.018. Epub 2021 Nov 10.

Authors

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

Affiliations

¹ Department of Immunobiology, Yale University, New Haven, CT 06520, USA; Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
² Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, Shandong 266071, China; Department of Reproductive Medicine, the Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China.
³ Aix-Marseille Universite, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy (CIML), 13288 Marseille Cedex 9, France.
⁴ Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China; Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA.
⁵ Institut für Chemie, Humboldt Universität zu Berlin, Berlin 12489, Germany; Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
⁶ Department of Genetics, Yale University, New Haven, CT 06520, USA; Center for Genome Analysis, Yale University, New Haven, CT 06510, USA.
⁷ Department of Cell Biology, Yale University, New Haven, CT 06520, USA.
⁸ Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA.
⁹ Department of Genetics, Yale University, New Haven, CT 06520, USA.
¹⁰ Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
¹¹ Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
¹² NOMIS Center for Immunobiology and Microbial Pathogenesis, the Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹³ Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada.
¹⁴ Institut für Chemie, Humboldt Universität zu Berlin, Berlin 12489, Germany.
¹⁵ Institute of Clinical Chemistry, University and University Hospital of Zurich, Zurich 8091, Switzerland.
¹⁶ NOMIS Center for Immunobiology and Microbial Pathogenesis, the Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: [email protected].
¹⁷ Center for Molecular Medicine, Department of Genetics, University of Georgia, Athens, GA 30602, USA. Electronic address: [email protected].
¹⁸ Department of Immunobiology, Yale University, New Haven, CT 06520, USA. Electronic address: [email protected].

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.

Keywords: 1-deoxysphingosine; COUP-TF; NR2F1; NR2F2; NR2F6; SPTLC2; cardiomyocyte; lymphatic; metabolism; sphingolipid.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / drug effects*
Cell Differentiation / physiology
Gene Expression Regulation / drug effects*
Gene Expression Regulation / physiology
Humans
Lymphatic Vessels / drug effects
Mice
Organogenesis / drug effects*
Organogenesis / physiology
Repressor Proteins / physiology
Sphingolipids / pharmacology*

Substances

1-deoxysphingolipid
Repressor Proteins
Sphingolipids

Abstract

Publication types

MeSH terms

Substances

Grants and funding