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Cell Metab. 2015 Feb 3;21(2):286-298. doi: 10.1016/j.cmet.2015.01.004.

Identification of natural RORγ ligands that regulate the development of lymphoid cells.

Author information

1
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: fsantof01@gmail.com.
2
Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
3
VU University Medical Center, Department of Molecular Cell Biology and Immunology, van der Boechorststraat 7, 1081BT Amsterdam, the Netherlands.
4
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
5
Center for Chemical Biology and Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
6
Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia.
7
Institute of Biochemistry, Center for Functional Genomics and Bio-chips, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia.
8
Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia; National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
9
Institut de Biologie Moleculaire des Plantes (IBMP), CNRS-UPR2357, 67083 Strasbourg, France.
10
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.

Abstract

Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.

PMID:
25651181
PMCID:
PMC4317570
DOI:
10.1016/j.cmet.2015.01.004
[Indexed for MEDLINE]
Free PMC Article

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