7xvn

Structural highlights

Function

RORG_MOUSE Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of cellular differentiation, immunity, peripheral circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts (PubMed:17666523, PubMed:19381306, PubMed:19965867, PubMed:21853531, PubMed:22789990, PubMed:23723244). Regulates the circadian expression of clock genes such as CRY1, BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner (PubMed:22753030). Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock (PubMed:22753030). Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA as positive or negative modulator of expression of genes encoding phase I and Phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as SULT1E1 (PubMed:21853531). Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC1 and PCK1. Regulates the rhythmic expression of PROX1 and promotes its nuclear localization.^{[1] [2] [3] [4] [5] [6] [7]} Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches (PubMed:10602018, PubMed:14691482, PubMed:16148126). Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus (PubMed:16990136, PubMed:18164222, PubMed:26607793). May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus (PubMed:9881970, PubMed:10602018, PubMed:14691482, PubMed:16148126, PubMed:16990136, PubMed:18164222). Plays an indispensable role in the induction of IFN-gamma dependent anti-mycobacterial systemic immunity (By similarity).[UniProtKB:P51449]^{[8] [9] [10] [11] [12] [13] [14]}

References

1. ↑ Kang HS, Angers M, Beak JY, Wu X, Gimble JM, Wada T, Xie W, Collins JB, Grissom SF, Jetten AM. Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics. 2007 Oct 22;31(2):281-94. PMID:17666523 doi:10.1152/physiolgenomics.00098.2007
2. ↑ Jetten AM. Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal. 2009;7:e003. PMID:19381306 doi:10.1621/nrs.07003
3. ↑ Wang Y, Kumar N, Solt LA, Richardson TI, Helvering LM, Crumbley C, Garcia-Ordonez RD, Stayrook KR, Zhang X, Novick S, Chalmers MJ, Griffin PR, Burris TP. Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem. 2010 Feb 12;285(7):5013-25. PMID:19965867 doi:10.1074/jbc.M109.080614
4. ↑ Meissburger B, Ukropec J, Roeder E, Beaton N, Geiger M, Teupser D, Civan B, Langhans W, Nawroth PP, Gasperikova D, Rudofsky G, Wolfrum C. Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma. EMBO Mol Med. 2011 Nov;3(11):637-51. PMID:21853531 doi:10.1002/emmm.201100172
5. ↑ Takeda Y, Jothi R, Birault V, Jetten AM. RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res. 2012 Sep 1;40(17):8519-35. PMID:22753030 doi:10.1093/nar/gks630
6. ↑ Solt LA, Burris TP. Action of RORs and their ligands in (patho)physiology. Trends Endocrinol Metab. 2012 Dec;23(12):619-27. PMID:22789990 doi:10.1016/j.tem.2012.05.012
7. ↑ Takeda Y, Jetten AM. Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic Nucleic Acids Res. 2013 Aug;41(14):6992-7008. PMID:23723244 doi:10.1093/nar/gkt447
8. ↑ Villey I, de Chasseval R, de Villartay JP. RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORgamma / TOR, is up-regulated by signaling through the pre-T cell receptor and binds to the TEA promoter. Eur J Immunol. 1999 Dec;29(12):4072-80. PMID:10602018 doi:<4072::AID-IMMU4072>3.0.CO;2-E 10.1002/(SICI)1521-4141(199912)29:12<4072::AID-IMMU4072>3.0.CO;2-E
9. ↑ Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004 Jan;5(1):64-73. PMID:14691482 doi:10.1038/ni1022
10. ↑ Xie H, Sadim MS, Sun Z. RORgammat recruits steroid receptor coactivators to ensure thymocyte survival. J Immunol. 2005 Sep 15;175(6):3800-9. PMID:16148126
11. ↑ Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006 Sep 22;126(6):1121-33. PMID:16990136 doi:http://dx.doi.org/10.1016/j.cell.2006.07.035
12. ↑ Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008 Jan;28(1):29-39. PMID:18164222 doi:10.1016/j.immuni.2007.11.016
13. ↑ Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, Kaminski J, Xiao S, Meyer Zu Horste G, Pawlak M, Kishi Y, Joller N, Karwacz K, Zhu C, Ordovas-Montanes M, Madi A, Wortman I, Miyazaki T, Sobel RA, Park H, Regev A, Kuchroo VK. CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell. 2015 Dec 3;163(6):1413-27. PMID:26607793 doi:10.1016/j.cell.2015.10.068
14. ↑ He YW, Deftos ML, Ojala EW, Bevan MJ. RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity. 1998 Dec;9(6):797-806. PMID:9881970 doi:10.1016/s1074-7613(00)80645-7