Two
isoforms are produced from the same RORC gene,[6] probably by selection of alternative promoters.[7][8]
RORγ (also referred to as RORγ1) – produced from an
mRNA containing
exons 1 to 11.[9]
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.[7]
RORγ
The
mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat.[5][10][11] 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.[12] Consistent with this, the main
phenotypes identified in RORγ-/-
knockout mice (where neither isoform is expressed) are those associated with RORγt immune system function[13] and an isoform specific RORγt knockout displayed a phenotype identical to the RORγ-/- knockout.[13] On the other hand, circadian phenotypes of RORγ-/- mice[14] 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).[15][16]
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. [13][17][18][19] RORγt inhibitors are under development for the treatment of autoimmune diseases such as
psoriasis and
rheumatoid arthritis.[12][20]
Function
The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of
nuclear receptors.[21] 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,[15][22] 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,[14] for example the cell cycle regulator
p21.[23] 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.[24][25][26]
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.[8][17][27] It is essential for the specific immune cells responsible for embryonic lymphoid formation, the Lymphoid Tissue inducer (LTi) cells.[13] 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.[28] 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.[17][27][29] 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 .[6]
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.[30]
Intermediates within the cholesterol pathway have been shown to activate RORγt.[32] Various
oxysterols are claimed to be an activator of RORγ, but with lower potency as cholesterol intermediates.[33][32]
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.[34]
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.[35][36]
^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.
PMID8973331.
S2CID45306810.
^
abHuang 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): 737–743.
doi:
10.1517/14728222.11.6.737.
PMID17504012.
S2CID42933457.
^Hu X, Wang Y, Hao LY, Liu X, Lesch CA, Sanchez BM, et al. (February 2015). "Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists". Nature Chemical Biology. 11 (2): 141–147.
doi:
10.1038/nchembio.1714.
PMID25558972.
^Fauber BP, Magnuson S (July 2014). "Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc)". Journal of Medicinal Chemistry. 57 (14): 5871–5892.
doi:
10.1021/jm401901d.
PMID24502334.
^Clinical trial number NCT02929862 for "Study of LYC-55716 in Adult Subjects With Locally Advanced or Metastatic Cancer" at
ClinicalTrials.gov