Language:

Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

Cell metabolism, 2015-02, Vol.21 (2), p.286-298 [Peer Reviewed Journal]

2015 Elsevier Inc. ;Copyright © 2015 Elsevier Inc. All rights reserved. ;2015 Elsevier Inc. All rights reserved. 2015 ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2015.01.004 ;PMID: 25651181

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells
Author: Santori, Fabio R. ; Huang, Pengxiang ; van de Pavert, Serge A. ; 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.
Subjects: Animals ; Cell Line ; Cholesterol - biosynthesis ; Drosophila melanogaster - cytology ; HEK293 Cells ; Humans ; Ligands ; Lymphocytes - metabolism ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism ; Sterol 14-Demethylase - deficiency ; Sterol 14-Demethylase - metabolism ; Sterols - chemistry ; Sterols - metabolism ; Th17 Cells
Is Part Of: Cell metabolism, 2015-02, Vol.21 (2), p.286-298
Description: 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. [Display omitted] •Sterols are necessary and sufficient to promote RORγ transcriptional activity•RORγ promoted transcription maps into the cholesterol biosynthetic pathway (CBP)•In the CBP, the RORγ ligand is downstream of lanosterol and upstream of zymosterol•Genetic manipulation of ligand biosynthetic enzymes affect RORγ functions in vivo RORγt-deficient mice lack lymph nodes and Th17 cells. Santori et al. show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription and that in mammalian cells RORγt ligand is a cholesterol biosynthetic intermediate. Furthermore, genetic manipulation of RORγt-ligand biosynthesis affects development of lymph nodes and Th17 cells.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 1550-4131
EISSN: 1932-7420
DOI: 10.1016/j.cmet.2015.01.004
PMID: 25651181
Source: MEDLINE
Cell Press Archives (Open access)

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Identification of Natural RORγ Ligands that Regulate the Development of Lymphoid Cells

2015 Elsevier Inc. ;Copyright © 2015 Elsevier Inc. All rights reserved. ;2015 Elsevier Inc. All rights reserved. 2015 ;ISSN: 1550-4131 ;EISSN: 1932-7420 ;DOI: 10.1016/j.cmet.2015.01.004 ;PMID: 25651181

Searching Remote Databases, Please Wait