RAR-related orphan receptor gamma
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC (RAR-related orphan receptor C) gene. RORγ is member of the nuclear receptor family of transcription factors.
- RORγ (also referred to as RORγ1) – produced from an mRNA containing exons 1 to 11.
- 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.
The mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat. 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. Consistent with this, the main phenotypes identified in RORγ-/- knockout mice (where neither isoform is expressed) are those associated with RORγt immune system function and an isoform specific RORγt knockout displayed a phenotype identical to the RORγ-/- knockout. On the other hand, circadian phenotypes of RORγ-/- mice 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 tissue distribution of the second isoform, RORγt, appears to be highly restricted to the thymus where it is expressed exclusively in immature CD4+/CD8+ thymocytes and in lymphoid tissue inducer (LTi) cells. RORγt inhibitors are under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis.
The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear receptors. Although the specific functions of this nuclear receptor have not been fully characterized yet, some roles emerge from the literature on the mouse gene.
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, 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, for example the cell cycle regulator p21.
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 particular lymph nodes and Peyer's patches, but not the spleen. 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. 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 .
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.
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.
- Hirose T, Smith RJ, Jetten AM (December 1994). "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): 1976–83. doi:10.1006/bbrc.1994.2902. PMID 7811290.
- He YW, Deftos ML, Ojala EW, Bevan MJ (December 1998). "RORγt, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells". Immunity. 9 (6): 797–806. doi:10.1016/S1074-7613(00)80645-7. PMC 2776668. PMID 9881970.
- Villey I, de Chasseval R, de Villartay JP (December 1999). "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): 4072–80. doi:10.1002/(SICI)1521-4141(199912)29:12<4072::AID-IMMU4072>3.0.CO;2-E. PMID 10602018.
- Eberl G, Littman DR (October 2003). "The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches". Immunological Reviews. 195: 81–90. doi:10.1034/j.1600-065X.2003.00074.x. PMID 12969312.
- Medvedev A, Chistokhina A, Hirose T, Jetten AM (November 1997). "Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene". Genomics. 46 (1): 93–102. doi:10.1006/geno.1997.4980. PMID 9403063.
- Medvedev A, Yan ZH, Hirose T, Giguère V, Jetten AM (November 1996). "Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element". Gene. 181 (1–2): 199–206. doi:10.1016/S0378-1119(96)00504-5. PMID 8973331.
- Ortiz MA, Piedrafita FJ, Pfahl M, Maki R (December 1995). "TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals". Molecular Endocrinology. 9 (12): 1679–91. doi:10.1210/me.9.12.1679. PMID 8614404.
- Huang Z, Xie H, Wang R, Sun Z (June 2007). "Retinoid-related orphan receptor gamma t is a potential therapeutic target for controlling inflammatory autoimmunity". Expert Opinion on Therapeutic Targets. 11 (6): 737–43. doi:10.1517/14728184.108.40.2067. PMID 17504012.
- Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR (January 2004). "An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells". Nature Immunology. 5 (1): 64–73. doi:10.1038/ni1022. PMID 14691482.
- Liu AC, Tran HG, Zhang EE, Priest AA, Welsh DK, Kay SA (February 2008). Takahashi JS, ed. "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. doi:10.1371/journal.pgen.1000023. PMC 2265523. PMID 18454201.
- Guillaumond F, Dardente H, Giguère V, Cermakian N (October 2005). "Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors". Journal of Biological Rhythms. 20 (5): 391–403. doi:10.1177/0748730405277232. PMID 16267379.
- Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (July 2002). "The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell. 110 (2): 251–60. doi:10.1016/S0092-8674(02)00825-5. PMID 12150932.
- Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR (June 2000). "Requirement for RORgamma in thymocyte survival and lymphoid organ development". Science. 288 (5475): 2369–73. doi:10.1126/science.288.5475.2369. PMID 10875923.
- Eberl G, Littman DR (July 2004). "Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells". Science. 305 (5681): 248–51. doi:10.1126/science.1096472. PMID 15247480.
- "Merck and Lycera to Develop Oral Autoimmune Disease Drugs Targeting Th17 Cells". Mar 2011.
- Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V (December 2006). "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacological Reviews. 58 (4): 798–836. doi:10.1124/pr.58.4.10. PMID 17132856.
- Akashi M, Takumi T (May 2005). "The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1". Nature Structural & Molecular Biology. 12 (5): 441–8. doi:10.1038/nsmb925. PMID 15821743.
- Gréchez-Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F (February 2008). "The circadian clock component BMAL1 is a critical regulator of p21WAF1/CIP1 expression and hepatocyte proliferation". The Journal of Biological Chemistry. 283 (8): 4535–42. doi:10.1074/jbc.M705576200. PMID 18086663.
- Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM (August 2000). "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): 10132–7. doi:10.1073/pnas.97.18.10132. PMC 27750. PMID 10963675.
- Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (Sep 2006). "The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells". Cell. 126 (6): 1121–33. doi:10.1016/j.cell.2006.07.035. PMID 16990136.
- Hegazy AN, Powrie F (2015). "MICROBIOME. Microbiota RORgulates intestinal suppressor T cells". Science. 349 (6251): 929–30. doi:10.1126/science.aad0865. PMID 26315421.
- Hu X, Wang Y, Hao LY, Liu X, Lesch CA, Sanchez BM, Wendling JM, Morgan RW, Aicher TD, Carter LL, Toogood PL, Glick GD (2015). "Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists". Nature Chemical Biology. 11 (2): 141–7. doi:10.1038/nchembio.1714. PMID 25558972.
- Fauber BP, Magnuson S (2014). "Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc)". Journal of Medicinal Chemistry. 57 (14): 5871–92. doi:10.1021/jm401901d. PMID 24502334.
- Clinical trial number NCT02929862 for "Study of LYC-55716 in Adult Subjects With Locally Advanced or Metastatic Cancer" at ClinicalTrials.gov
- "Lycera Announces Initiation of Phase 1b Study of Novel Immuno-Oncology Candidate LYC-55716 in Combination with Pembrolizumab". January 2018.