Avtor/Urednik		Santori, Fabio R.; Huang, Pengxiang; Pavert, Serge A. van de; Douglass, Eugene F.; Leaver, David J.; Haubrich, Brad A.; Keber, Rok; Lorbek, Gregor; Konijn, Tanja; Rosales, Brittany N.; Rozman, Damjana; Horvat, Simon; Rahier, Alain; Mebius, Reina E.; Rastinejad, Fraydoon; Nes, W. David; Littman, Dan R.
Naslov		Identification of natural ROR[gamma] ligands that regulate the development of lymphoid cells
Tip		članek
Vol. in št.		Letnik 21, št. 2
Leto izdaje		2015
Obseg		str. 286-297
ISSN		1550-4131 - Cell metabolism
Jezik		eng
Abstrakt		Mice deficient in the nuclear hormone receptor ROR[gamma]t have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. ROR[gamma]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[gamma]t-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study ROR[gamma]-dependent transcription. Our results are consistent with the ROR[gamma]t ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to ROR[gamma] identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the ROR[gamma] ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the ROR[gamma]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[gamma].
Proste vsebinske oznake		imunologija limfoidne celice holesterol