RAR-related orphan receptor explained

Hgncid:	10258
Symbol:	RORA
Altsymbols:	RZRA, ROR1, ROR2, ROR3, NR1F1
Entrezgene:	6095
Omim:	600825
Refseq:	NM_002943
Uniprot:	P35398
Pdb:	1N83
Chromosome:	15
Arm:	q
Band:	21
Locussupplementarydata:	-q22

Hgncid:	10259
Symbol:	RORB
Altsymbols:	RZRB, NR1F2, ROR-BETA
Entrezgene:	6096
Omim:	601972
Refseq:	NM_006914
Uniprot:	Q92753
Pdb:	1NQ7
Chromosome:	9
Arm:	q
Band:	22

Hgncid:	10260
Symbol:	RORC
Altsymbols:	RZRG, RORG, NR1F3, TOR
Entrezgene:	6097
Omim:	602943
Refseq:	NM_005060
Uniprot:	P51449
Chromosome:	1
Arm:	q
Band:	21

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]

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. Side chain oxygenated sterols (e.g., 20α-hydroxycholesterol, 22R-hydroxycholesterol, and 25-hydroxycholesterol) are high affinity RORγ agonists while sterols oxygenated at the 7-position, (e.g., (7-hydroxycholesterol and 7-ketocholesterol) function as inverse agonists for both RORa and RORγ. 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.^[7] Finally the RORs may function as lipid sensors and hence may play a role in the regulation of lipid metabolism.

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.^[8]

Tissue distribution

RORα, RORβ, and RORγ are primarily expressed the following tissues:^[9]

• 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:

• ROR-α – Involved in the maintenance of the circadian rhythm by positively regulating the expression of BMAL1. Development of the cerebellum and lymph nodes, lipid metabolism, immune response, maintenance of bone.^[11]
• ROR-β – Circadian rhythm, bone metabolism, and retinal neurogenesis.^[12]
• ROR-γ – Lymph node development and immune response, survival of T helper 17 cells.

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]}

See also

• Retinoid receptor

Further reading

• Solt LA, Griffin PR, Burris TP . Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics . Current Opinion in Lipidology . 21 . 3 . 204–11 . June 2010 . 20463469 . 5024716 . 10.1097/MOL.0b013e328338ca18 .
• Book: Chang MR, Rosen H, Griffin PR . Sphingosine-1-Phosphate Signaling in Immunology and Infectious Diseases . RORs in Autoimmune Disease . Current Topics in Microbiology and Immunology . 378 . 171–82 . 2014 . 24728598 . 10.1007/978-3-319-05879-5_8 . 978-3-319-05878-8 .

Notes and References

1. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G . 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 . March 1994 . 7926749 . 10.1101/gad.8.5.538 . free .
2. Hirose T, Smith RJ, Jetten AM . 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 . December 1994 . 7811290 . 10.1006/bbrc.1994.2902 .
3. Book: Jetten AM, Kurebayashi S, Ueda E . The ROR nuclear orphan receptor subfamily: critical regulators of multiple biological processes . 69 . 205–47 . 2001 . 11550795 . 10.1016/S0079-6603(01)69048-2 . 978-0-12-540069-5 . Progress in Nucleic Acid Research and Molecular Biology .
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. 10.1016/s0079-6603(01)69048-2. 0079-6603. 11550795. 9780125400695.
5. Solt LA, Burris TP . Action of RORs and their ligands in (patho)physiology . Trends in Endocrinology and Metabolism . 23 . 12 . 619–27 . December 2012 . 22789990 . 3500583 . 10.1016/j.tem.2012.05.012 .
6. Santori FR . Nuclear hormone receptors put immunity on sterols . European Journal of Immunology . 45 . 10 . 2730–41 . 2015 . 26222181 . 4651655 . 10.1002/eji.201545712 .
7. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R . All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta . Nature Structural Biology . 10 . 10 . 820–5 . October 2003 . 12958591 . 10.1038/nsb979 . 10108247 .
8. Wiesenberg I, Missbach M, Kahlen JP, Schräder M, Carlberg C . 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 . February 1995 . 7885826 . 306679 . 10.1093/nar/23.3.327 .
9. Zhang Y, Luo XY, Wu DH, Xu Y . ROR nuclear receptors: structures, related diseases, and drug discovery . Acta Pharmacologica Sinica . 36 . 1 . 71–87 . January 2015 . 25500868 . 4571318 . 10.1038/aps.2014.120 .
10. Jetten AM . 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 . December 2004 . 15584888 . 10.2174/1568010042634497 .
11. Jetten AM, Joo JH . Retinoid-related Orphan Receptors (RORs): Roles in Cellular Differentiation and Development . Advances in Developmental Biology (Amsterdam, Netherlands) . 16 . 313–355 . 2006 . 18418469 . 2312092 . 10.1016/S1574-3349(06)16010-X . Advances in Developmental Biology . 9780444528735 .
12. Feng S, Xu S, Wen Z, Zhu Y . Retinoic acid-related orphan receptor RORβ, circadian rhythm abnormalities and tumorigenesis (Review) . International Journal of Molecular Medicine . 35 . 6 . 1493–500 . 2015 . 25816151 . 10.3892/ijmm.2015.2155 . free .
13. Cyr P, Bronner SM, Crawford JJ . Recent progress on nuclear receptor RORγ modulators . Bioorganic & Medicinal Chemistry Letters . 26 . 18 . 4387–93 . 2016 . 27542308 . 10.1016/j.bmcl.2016.08.012 .
14. Bronner SM, Zbieg JR, Crawford JJ . RORγ antagonists and inverse agonists: a patent review . Expert Opinion on Therapeutic Patents . 27 . 1 . 101–112 . 2017 . 27629281 . 10.1080/13543776.2017.1236918 . 27177212 .