| Structural highlights
Function
[RORA_HUMAN] Orphan nuclear receptor. Binds DNA as a monomer to hormone response elements (HRE) containing a single core motif half-site preceded by a short A-T-rich sequence. This isomer binds to the consensus sequence 5'-[AT][TA]A[AT][CGT]TAGGTCA-3'. Regulates a number of genes involved in lipid metabolism such as apolipoproteins AI, APOA5, CIII, CYP71 and PPARgamma, in cerebellum and photoreceptor development including PCP2, OPN1SW, OPN1SM AND ARR3, in circadian rhythm with BMAL1, and skeletal muscle development with MYOD1. Possible receptor for cholesterol or one of its derivatives.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [NRIP1_HUMAN] Modulates transcriptional activation by steroid receptors such as NR3C1, NR3C2 and ESR1. Also modulates transcriptional repression by nuclear hormone receptors.[11] [12] [13] [14] [15] [16]
Publication Abstract from PubMed
Mice deficient in the nuclear hormone receptor RORgammat have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORgammat 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 RORgammat-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORgamma-dependent transcription. Our results are consistent with the RORgammat ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORgamma identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORgamma ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORgammat-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 RORgammat.
Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells.,Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Sundvold H, Lien S. Identification of a novel peroxisome proliferator-activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor RORalpha1. Biochem Biophys Res Commun. 2001 Sep 21;287(2):383-90. PMID:11554739 doi:http://dx.doi.org/10.1006/bbrc.2001.5602
- ↑ Raspe E, Duez H, Gervois P, Fievet C, Fruchart JC, Besnard S, Mariani J, Tedgui A, Staels B. Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha. J Biol Chem. 2001 Jan 26;276(4):2865-71. Epub 2000 Oct 26. PMID:11053433 doi:http://dx.doi.org/10.1074/jbc.M004982200
- ↑ Moraitis AN, Giguere V. The co-repressor hairless protects RORalpha orphan nuclear receptor from proteasome-mediated degradation. J Biol Chem. 2003 Dec 26;278(52):52511-8. Epub 2003 Oct 21. PMID:14570920 doi:http://dx.doi.org/10.1074/jbc.M308152200
- ↑ Genoux A, Dehondt H, Helleboid-Chapman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, Fruchart JC. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha. Arterioscler Thromb Vasc Biol. 2005 Jun;25(6):1186-92. Epub 2005 Mar 24. PMID:15790933 doi:http://dx.doi.org/10.1161/01.ATV.0000163841.85333.83
- ↑ Lind U, Nilsson T, McPheat J, Stromstedt PE, Bamberg K, Balendran C, Kang D. Identification of the human ApoAV gene as a novel RORalpha target gene. Biochem Biophys Res Commun. 2005 Apr 29;330(1):233-41. PMID:15781255 doi:http://dx.doi.org/10.1016/j.bbrc.2005.02.151
- ↑ Lechtken A, Hornig M, Werz O, Corvey N, Zundorf I, Dingermann T, Brandes R, Steinhilber D. Extracellular signal-regulated kinase-2 phosphorylates RORalpha4 in vitro. Biochem Biophys Res Commun. 2007 Jul 6;358(3):890-6. Epub 2007 May 11. PMID:17512500 doi:http://dx.doi.org/10.1016/j.bbrc.2007.05.016
- ↑ Kim EJ, Yoo YG, Yang WK, Lim YS, Na TY, Lee IK, Lee MO. Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling. Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1796-802. doi:, 10.1161/ATVBAHA.108.171546. Epub 2008 Jul 24. PMID:18658046 doi:http://dx.doi.org/10.1161/ATVBAHA.108.171546
- ↑ Duplus E, Gras C, Soubeyre V, Vodjdani G, Lemaigre-Dubreuil Y, Brugg B. Phosphorylation and transcriptional activity regulation of retinoid-related orphan receptor alpha 1 by protein kinases C. J Neurochem. 2008 Mar;104(5):1321-32. Epub 2007 Nov 10. PMID:18005000 doi:http://dx.doi.org/10.1111/j.1471-4159.2007.05074.x
- ↑ Kallen JA, Schlaeppi JM, Bitsch F, Geisse S, Geiser M, Delhon I, Fournier B. X-ray structure of the hRORalpha LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. Structure. 2002 Dec;10(12):1697-707. PMID:12467577
- ↑ Cavailles V, Dauvois S, L'Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG. Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J. 1995 Aug 1;14(15):3741-51. PMID:7641693
- ↑ Subramaniam N, Treuter E, Okret S. Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids. J Biol Chem. 1999 Jun 18;274(25):18121-7. PMID:10364267
- ↑ Vo N, Fjeld C, Goodman RH. Acetylation of nuclear hormone receptor-interacting protein RIP140 regulates binding of the transcriptional corepressor CtBP. Mol Cell Biol. 2001 Sep;21(18):6181-8. PMID:11509661
- ↑ Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombes M. A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol. 2001 Sep;15(9):1586-98. PMID:11518808
- ↑ Teyssier C, Belguise K, Galtier F, Cavailles V, Chalbos D. Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Mol Endocrinol. 2003 Feb;17(2):287-99. PMID:12554755 doi:http://dx.doi.org/10.1210/me.2002-0324
- ↑ Castet A, Boulahtouf A, Versini G, Bonnet S, Augereau P, Vignon F, Khochbin S, Jalaguier S, Cavailles V. Multiple domains of the Receptor-Interacting Protein 140 contribute to transcription inhibition. Nucleic Acids Res. 2004 Apr 1;32(6):1957-66. Print 2004. PMID:15060175 doi:http://dx.doi.org/10.1093/nar/gkh524
- ↑ Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR. Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells. Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181 doi:http://dx.doi.org/10.1016/j.cmet.2015.01.004
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