Identification of natural ROR? ligands that regulate the development of lymphoid cells.

ABSTRACT: Mice deficient in the nuclear hormone receptor ROR?t have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. ROR?t 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 ROR?t-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study ROR?-dependent transcription. Our results are consistent with the ROR?t ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to ROR? identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the ROR? ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the ROR?t-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 ROR?t.

SUBMITTER: Santori FR 

PROVIDER: S-EPMC4317570 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature