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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.

Original publication

DOI

10.1016/j.cmet.2015.01.004

Type

Journal article

Journal

Cell Metab

Publication Date

03/02/2015

Volume

21

Pages

286 - 298

Keywords

Animals, Cell Line, Cholesterol, Drosophila melanogaster, HEK293 Cells, Humans, Ligands, Lymphocytes, Male, Mice, Mice, Knockout, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 3, Sterol 14-Demethylase, Sterols, Th17 Cells