RAR-related orphan receptor

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors.[1][2] There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers.[3] They bind to DNA elements called ROR response elements (RORE).[4]

RAR-related orphan receptor A (alpha)
Identifiers
SymbolRORA
Alt. symbolsRZRA, ROR1, ROR2, ROR3, NR1F1
NCBI gene6095
HGNC10258
OMIM600825
PDB1N83
RefSeqNM_002943
UniProtP35398
Other data
LocusChr. 15 q21-q22
RAR-related orphan receptor B (beta)
Identifiers
SymbolRORB
Alt. symbolsRZRB, NR1F2, ROR-BETA
NCBI gene6096
HGNC10259
OMIM601972
PDB1NQ7
RefSeqNM_006914
UniProtQ92753
Other data
LocusChr. 9 q22
RAR-related orphan receptor C (gamma)
Identifiers
SymbolRORC
Alt. symbolsRZRG, RORG, NR1F3, TOR
NCBI gene6097
HGNC10260
OMIM602943
RefSeqNM_005060
UniProtP51449
Other data
LocusChr. 1 q21

Ligands

While the identity of natural ligands for the RORs remains controversial, similar to the liver X receptors (LXRs), it appears that the RORs are activated by oxysterols.[5][6] Furthermore, the RORs appear to be constitutively active (absence of ligand) and that activity may be due to continuously bound natural ligands.[5] Side chain oxygenated sterols (e.g., 20α-hydroxycholesterol, 22R-hydroxycholesterol, and 25-hydroxycholesterol) are high affinity RORγ agonists[7] while sterols oxygenated at the 7-position, (e.g., (7-hydroxycholesterol and 7-ketocholesterol) function as inverse agonists for both RORa and RORγ.[5] A number of other natural substances have also been reported to bind to the RORs. These include all-trans retinoic acid binds with high affinity to ROR-β and -γ but not ROR-α.[8] Finally the RORs may function as lipid sensors and hence may play a role in the regulation of lipid metabolism.[5]

Melatonin has been claimed to be an endogenous ligand for ROR-α while CGP 52608 has been identified as a ROR-α selective synthetic ligand.[9]

Tissue distribution

RORα, RORβ, and RORγ are primarily expressed the following tissues:[7]

  • ROR-α – widely expressed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, and brain.
  • ROR-β – expression restricted to the brain and retina.
  • ROR-γ – highly expressed in thymus (the thymus-specific isoform is referred to as RORγt), muscle, testis, pancreas, prostate, heart, and liver.

Function

The three forms of RORs fulfill a number of critical roles[10] including:

As drug targets

A number of synthetic RORγt inverse agonists are in various stages of drug development for the treatment of inflammatory diseases. RORγt agonists have also been proposed for use as immunooncology agents to activate the immune system to treat cancer.[13][14]

References
  1. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G (March 1994). "Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors". Genes & Development. 8 (5): 538–53. doi:10.1101/gad.8.5.538. PMID 7926749.
  2. 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.
  3. Jetten AM, Kurebayashi S, Ueda E (2001). The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes. Progress in Nucleic Acid Research and Molecular Biology. 69. pp. 205–47. doi:10.1016/S0079-6603(01)69048-2. ISBN 978-0-12-540069-5. PMID 11550795.
  4. Jetten, A. M.; Kurebayashi, S.; Ueda, E. (2001). "The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes". Progress in Nucleic Acid Research and Molecular Biology. 69: 205–247. doi:10.1016/s0079-6603(01)69048-2. ISBN 9780125400695. ISSN 0079-6603. PMID 11550795.
  5. Solt LA, Burris TP (December 2012). "Action of RORs and their ligands in (patho)physiology". Trends in Endocrinology and Metabolism. 23 (12): 619–27. doi:10.1016/j.tem.2012.05.012. PMC 3500583. PMID 22789990.
  6. Santori FR (2015). "Nuclear hormone receptors put immunity on sterols". European Journal of Immunology. 45 (10): 2730–41. doi:10.1002/eji.201545712. PMC 4651655. PMID 26222181.
  7. Zhang Y, Luo XY, Wu DH, Xu Y (January 2015). "ROR nuclear receptors: structures, related diseases, and drug discovery". Acta Pharmacologica Sinica. 36 (1): 71–87. doi:10.1038/aps.2014.120. PMC 4571318. PMID 25500868.
  8. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R (October 2003). "All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta". Nature Structural Biology. 10 (10): 820–5. doi:10.1038/nsb979. PMID 12958591. S2CID 10108247.
  9. Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C (February 1995). "Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand". Nucleic Acids Research. 23 (3): 327–33. doi:10.1093/nar/23.3.327. PMC 306679. PMID 7885826.
  10. Jetten AM (December 2004). "Recent advances in the mechanisms of action and physiological functions of the retinoid-related orphan receptors (RORs)". Current Drug Targets. Inflammation and Allergy. 3 (4): 395–412. doi:10.2174/1568010042634497. PMID 15584888.
  11. Jetten AM, Joo JH (2006). "Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development". Advances in Developmental Biology (Amsterdam, Netherlands). Advances in Developmental Biology. 16: 313–355. doi:10.1016/S1574-3349(06)16010-X. ISBN 9780444528735. PMC 2312092. PMID 18418469.
  12. Feng S, Xu S, Wen Z, Zhu Y (2015). "Retinoic acid-related orphan receptor RORβ, circadian rhythm abnormalities and tumorigenesis (Review)". International Journal of Molecular Medicine. 35 (6): 1493–500. doi:10.3892/ijmm.2015.2155. PMID 25816151.
  13. Cyr P, Bronner SM, Crawford JJ (2016). "Recent progress on nuclear receptor RORγ modulators". Bioorganic & Medicinal Chemistry Letters. 26 (18): 4387–93. doi:10.1016/j.bmcl.2016.08.012. PMID 27542308.
  14. Bronner SM, Zbieg JR, Crawford JJ (2017). "RORγ antagonists and inverse agonists: a patent review". Expert Opinion on Therapeutic Patents. 27 (1): 101–112. doi:10.1080/13543776.2017.1236918. PMID 27629281. S2CID 27177212.

Further reading
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