title: Identification of natural RORγ ligands that regulate the development of lymphoid cells.
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.
authors: 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.
authors: Fabio R
authors: FR
authors: Santori
authors: Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Pengxiang
authors: P
authors: Huang
authors: VU University Medical Center, Department of Molecular Cell Biology and Immunology, van der Boechorststraat 7, 1081BT Amsterdam, the Netherlands.
authors: Serge A
authors: SA
authors: van de Pavert
authors: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors: Eugene F
authors: EF
authors: Douglass
authors: Center for Chemical Biology and Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
authors: David J
authors: DJ
authors: Leaver
authors: Center for Chemical Biology and Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
authors: Brad A
authors: BA
authors: Haubrich
authors: Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia.
authors: Rok
authors: R
authors: Keber
authors: Institute of Biochemistry, Center for Functional Genomics and Bio-chips, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia.
authors: Gregor
authors: G
authors: Lorbek
authors: VU University Medical Center, Department of Molecular Cell Biology and Immunology, van der Boechorststraat 7, 1081BT Amsterdam, the Netherlands.
authors: Tanja
authors: T
authors: Konijn
authors: Center for Chemical Biology and Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
authors: Brittany N
authors: BN
authors: Rosales
authors: Institute of Biochemistry, Center for Functional Genomics and Bio-chips, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia.
authors: Damjana
authors: D
authors: Rozman
authors: Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230 Domzale, Slovenia; National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors: Simon
authors: S
authors: Horvat
authors: Institut de Biologie Moleculaire des Plantes (IBMP), CNRS-UPR2357, 67083 Strasbourg, France.
authors: Alain
authors: A
authors: Rahier
authors: VU University Medical Center, Department of Molecular Cell Biology and Immunology, van der Boechorststraat 7, 1081BT Amsterdam, the Netherlands.
authors: Reina E
authors: RE
authors: Mebius
authors: Metabolic Disease Program, Sanford-Burnham Medical Research Institute, 6400 Sanger Road, Orlando, FL 32827, USA.
authors: Fraydoon
authors: F
authors: Rastinejad
authors: Center for Chemical Biology and Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409, USA.
authors: W David
authors: WD
authors: Nes
authors: 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.
authors: Dan R
authors: DR
authors: Littman
mesh_terms: D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis; D004331:Drosophila melanogaster / Q000166:cytology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D058886:Sterol 14-Demethylase / Q000172:deficiency / Q000378:metabolism; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D058504:Th17 Cells
chemical_list: D008024:Ligands; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013261:Sterols; D002784:Cholesterol; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase
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