1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.
1-deoxysphingosine
COUP-TF
NR2F1
NR2F2
NR2F6
SPTLC2
cardiomyocyte
lymphatic
metabolism
sphingolipid
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
22 11 2021
22 11 2021
Historique:
received:
02
08
2020
revised:
30
08
2021
accepted:
19
10
2021
pubmed:
12
11
2021
medline:
15
12
2021
entrez:
11
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34762852
pii: S1534-5807(21)00849-2
doi: 10.1016/j.devcel.2021.10.018
pmc: PMC8628544
mid: NIHMS1753718
pii:
doi:
Substances chimiques
1-deoxysphingolipid
0
Repressor Proteins
0
Sphingolipids
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3128-3145.e15Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM107092
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM137782
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI131015
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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