Biology:RAR-related orphan receptor gamma

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Short description: Cellular receptor


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC (RAR-related orphan receptor C) gene.[1] RORγ is a member of the nuclear receptor family of transcription factors. It is mainly expressed in immune cells (Th17 cells) and it also regulates circadian rhythms. It may be involved in the progression of certain types of cancer.

Gene expression

Two isoforms are produced from the same RORC gene,[2] probably by selection of alternative promoters.[3][4]

  • RORγ (also referred to as RORγ1) – produced from an mRNA containing exons 1 to 11.[5]
  • RORγt (also known as RORγ2) – produced from an mRNA identical to that of RORγ, except that the two 5'-most exons are replaced by an alternative exon, located downstream in the gene. This causes a different, shorter N-terminus.[3]

RORγ

The mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat.[1][6][7] While RORγ mRNA is abundantly expressed, attempts to detect RORγ protein have not been successful; therefore it is not clear whether RORγ protein is actually expressed.[8] Consistent with this, the main phenotypes identified in RORγ-/- knockout mice (where neither isoform is expressed) are those associated with RORγt immune system function[9] and an isoform specific RORγt knockout displayed a phenotype identical to the RORγ-/- knockout.[9] On the other hand, circadian phenotypes of RORγ-/- mice[10] in tissues where the RORγt isoform is expressed in minute amounts argues for the expression of functional RORγ isoform. Absent protein in previous studies may be due to the high amplitude circadian rhythm of expression of this isoform in some tissues.

The mRNA is expressed in various peripheral tissues, either in a circadian fashion (e.g., in the liver and kidney) or constitutively (e.g., in the muscle).[11][12]

In contrast to other ROR genes, the RORC gene is not expressed in the central nervous system.

RORγt

The second isoform, RORγt, is expressed in various immune cells. Of those, the most prominent examples are immature CD4+/CD8+ thymocytes, T helper 17 (Th17) cells and in type 3 innate lymphoid cells (ILC3). Mice lacking RORγt are devoid of lymph nodes and Peyer's patches due to the lack of Lymphoid tissue inducer cells (LTi), a subpopulation of ILC3s and important drivers of lymphoid organogenesis. [9][13][14][15] RORγt inhibitors are under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis.[8][16]

Function

The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear receptors.[17] Although the specific functions of this nuclear receptor have not been fully characterized yet, some roles emerge from the literature on the mouse gene.

Circadian rhythms

The RORγ isoform appears to be involved in the regulation of circadian rhythms. This protein can bind to and activate the promoter of the ARNTL (BMAL1) gene,[11][18] a transcription factor central to the generation of physiological circadian rhythms. Also, since the levels of RORγ are rhythmic in some tissues (liver, kidney), it has been proposed to impose a circadian pattern of expression on a number of clock-controlled genes,[10] for example the cell cycle regulator p21.[19] Conversely, it has also been demonstrated that RORγt+ enteric ILC3s themselves are under circadian control, being entrained by light that is sensed by the suprachiasmatic nucleus. Importantly, the deletion of ARNTL in ILC3s using a RORc promoter disrupted enteric defence, reinforcing the role of clock machinery in the control of RORγt. Whilst ILC3s themselves oscillate in a circadian manner and exhibit diurnal variations in the expression of clock genes, it remains unclear exactly how the central clock relays these signals to the RORγt+ ILC3s in the gut.[20][21][22]

Immune regulation

RORγt is the most studied of the two isoforms. Its best understood functionality is in the immune system. The transcription factor is essential for lymphoid organogenesis in the embryo, in particular lymph nodes and Peyer's patches, but not the spleen.[4][13][23] It is essential for the specific immune cells responsible for embryonic lymphoid formation, the Lymphoid Tissue inducer (LTi) cells.[9] Within these cells, retinoic acid induces expression of RORc. Consequently, removing the metabolic ground product for retinoic acid, vitamin A, from the diet of pregnant mice resulted in lower embryonic LTi cell differentiation, leading to smaller lymph nodes in the adult offspring and finally resulting in lower capabilities to clear a virus.[24] RORγt also plays an important regulatory role in thymopoiesis, by reducing apoptosis of thymocytes and promoting thymocyte differentiation into pro-inflammatory T helper 17 (Th17) cells.[13][23][25] It also plays a role in inhibiting apoptosis of undifferentiated T cells and promoting their differentiation into Th17 cells, possibly by down regulating the expression of Fas ligand and IL2, respectively .[2]

Despite the pro-inflammatory role of RORγt in the thymus, it is expressed in a Treg cell subpopulation in the colon, and is induced by symbiotic microflora. Abrogation of the gene's activity generally increases type 2 cytokines and may make mice more vulnerable to oxazolone-induced colitis.[26]

Cancer

RORγ is expressed in certain subsets of cancer stem cells (EpCAM+/MSI2+) in pancreatic cancer and shows a strong correlation with tumor stage and lymph node invasion.[27] Amplification of the RORC gene has also been observed in other malignancies such as lung, breast and neuroendocrine prostate cancer.[27]

Ligands

Intermediates within the cholesterol pathway have been shown to activate RORγt.[28] Various oxysterols are claimed to be an activator of RORγ, but with lower potency as cholesterol intermediates.[29][28]

As a drug target

As antagonism of the RORγ receptor may have therapeutic applications in the treatment of inflammatory diseases, a number of synthetic RORγ receptor antagonists have been developed.[30]

Agonists may allow the immune system to combat cancer. LYC-55716 is an oral, selective RORγ (RORgamma) agonist in clinical trials on patients with solid tumors.[31][32]

See also

References

  1. ↑ 1.0 1.1 "ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle". Biochemical and Biophysical Research Communications 205 (3): 1976–1983. December 1994. doi:10.1006/bbrc.1994.2902. PMID 7811290. https://zenodo.org/record/1229422. 
  2. ↑ 2.0 2.1 "RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells". Immunity 9 (6): 797–806. December 1998. doi:10.1016/S1074-7613(00)80645-7. PMID 9881970. 
  3. ↑ 3.0 3.1 "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". European Journal of Immunology 29 (12): 4072–4080. December 1999. doi:10.1002/(SICI)1521-4141(199912)29:12<4072::AID-IMMU4072>3.0.CO;2-E. PMID 10602018. 
  4. ↑ 4.0 4.1 "The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches". Immunological Reviews 195: 81–90. October 2003. doi:10.1034/j.1600-065X.2003.00074.x. PMID 12969312. 
  5. ↑ "Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene". Genomics 46 (1): 93–102. November 1997. doi:10.1006/geno.1997.4980. PMID 9403063. https://zenodo.org/record/1229743. 
  6. ↑ "Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element". Gene 181 (1–2): 199–206. November 1996. doi:10.1016/S0378-1119(96)00504-5. PMID 8973331. 
  7. ↑ "TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals". Molecular Endocrinology 9 (12): 1679–1691. December 1995. doi:10.1210/mend.9.12.8614404. PMID 8614404. 
  8. ↑ 8.0 8.1 "Retinoid-related orphan receptor gamma t is a potential therapeutic target for controlling inflammatory autoimmunity". Expert Opinion on Therapeutic Targets 11 (6): 737–743. June 2007. doi:10.1517/14728222.11.6.737. PMID 17504012. 
  9. ↑ 9.0 9.1 9.2 9.3 "An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells". Nature Immunology 5 (1): 64–73. January 2004. doi:10.1038/ni1022. PMID 14691482. https://hal-pasteur.archives-ouvertes.fr/pasteur-01402773/file/ni1022.pdf. 
  10. ↑ 10.0 10.1 "Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms". PLOS Genetics 4 (2): e1000023. February 2008. doi:10.1371/journal.pgen.1000023. PMID 18454201. 
  11. ↑ 11.0 11.1 "Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors". Journal of Biological Rhythms 20 (5): 391–403. October 2005. doi:10.1177/0748730405277232. PMID 16267379. 
  12. ↑ "The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell 110 (2): 251–260. July 2002. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932. 
  13. ↑ 13.0 13.1 13.2 "Requirement for RORgamma in thymocyte survival and lymphoid organ development". Science 288 (5475): 2369–2373. June 2000. doi:10.1126/science.288.5475.2369. PMID 10875923. Bibcode: 2000Sci...288.2369S. 
  14. ↑ "Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells". Science 305 (5681): 248–251. July 2004. doi:10.1126/science.1096472. PMID 15247480. Bibcode: 2004Sci...305..248E. 
  15. ↑ "Lineage relationship analysis of RORgammat+ innate lymphoid cells". Science 330 (6004): 665–669. October 2010. doi:10.1126/science.1194597. PMID 20929731. Bibcode: 2010Sci...330..665S. 
  16. ↑ "Merck and Lycera to Develop Oral Autoimmune Disease Drugs Targeting Th17 Cells". Mar 2011. http://www.genengnews.com/gen-news-highlights/merck-and-lycera-to-develop-oral-autoimmune-disease-drugs-targeting-th17-cells/81244770/. 
  17. ↑ "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacological Reviews 58 (4): 798–836. December 2006. doi:10.1124/pr.58.4.10. PMID 17132856. 
  18. ↑ "The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1". Nature Structural & Molecular Biology 12 (5): 441–448. May 2005. doi:10.1038/nsmb925. PMID 15821743. 
  19. ↑ "The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation". The Journal of Biological Chemistry 283 (8): 4535–4542. February 2008. doi:10.1074/jbc.M705576200. PMID 18086663. 
  20. ↑ "Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis". Nature 574 (7777): 254–258. October 2019. doi:10.1038/s41586-019-1579-3. PMID 31534216. Bibcode: 2019Natur.574..254G. 
  21. ↑ "A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut". Science Immunology 4 (40): eaax1215. October 2019. doi:10.1126/sciimmunol.aax1215. PMID 31586011. 
  22. ↑ "Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells". Science Immunology 4 (40): eaay7501. October 2019. doi:10.1126/sciimmunol.aay7501. PMID 31586012. 
  23. ↑ 23.0 23.1 "Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis". Proceedings of the National Academy of Sciences of the United States of America 97 (18): 10132–10137. August 2000. doi:10.1073/pnas.97.18.10132. PMID 10963675. Bibcode: 2000PNAS...9710132K. 
  24. ↑ "Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity". Nature 508 (7494): 123–127. April 2014. doi:10.1038/nature13158. PMID 24670648. Bibcode: 2014Natur.508..123V. 
  25. ↑ "The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells". Cell 126 (6): 1121–1133. September 2006. doi:10.1016/j.cell.2006.07.035. PMID 16990136. 
  26. ↑ "MICROBIOME. Microbiota RORgulates intestinal suppressor T cells". Science 349 (6251): 929–930. August 2015. doi:10.1126/science.aad0865. PMID 26315421. 
  27. ↑ 27.0 27.1 "A Multiscale Map of the Stem Cell State in Pancreatic Adenocarcinoma". Cell 177 (3): 572–586.e22. April 2019. doi:10.1016/j.cell.2019.03.010. PMID 30955884. 
  28. ↑ 28.0 28.1 "Identification of natural RORγ ligands that regulate the development of lymphoid cells". Cell Metabolism 21 (2): 286–298. February 2015. doi:10.1016/j.cmet.2015.01.004. PMID 25651181. 
  29. ↑ "Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists". Nature Chemical Biology 11 (2): 141–147. February 2015. doi:10.1038/nchembio.1714. PMID 25558972. 
  30. ↑ "Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc)". Journal of Medicinal Chemistry 57 (14): 5871–5892. July 2014. doi:10.1021/jm401901d. PMID 24502334. 
  31. ↑ Clinical trial number NCT02929862 for "Study of LYC-55716 in Adult Subjects With Locally Advanced or Metastatic Cancer" at ClinicalTrials.gov
  32. ↑ "Lycera Announces Initiation of Phase 1b Study of Novel Immuno-Oncology Candidate LYC-55716 in Combination with Pembrolizumab". January 2018. http://markets.businessinsider.com/news/stocks/Lycera-Announces-Initiation-of-Phase-1b-Study-of-Novel-Immuno-Oncology-Candidate-LYC-55716-in-Combination-with-Pembrolizumab-1012472060. 

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