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 a member of the nuclear receptor family of transcription factors, and 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.
Two isoforms are produced from the same RORC gene.
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.
The mRNA of the first isoform, RORγ is expressed in many tissues, including thymus, lung, liver, kidney, muscle, and brown fat.
The mRNA is expressed in peripheral tissues, either in a circadian fashion as in the liver and kidney, or constitutively in the muscle.
The RORC gene is not expressed in the central nervous system.
The second isoform, RORγt, is expressed in various immune Cells: immature CD4+/CD8+ thymocytes, T helper 17 (Th17) cells and in type 3 innate lymphoid cells (ILC3).
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.
The RORγ isoform appears to be involved in the regulation of circadian rhythms.
This protein can bind to and activate the promoter of a transcription gene factor central to the generation of physiological circadian rhythms.
The levels of RORγ are rhythmic in some tissues, such as the liver, kidney, and is proposed to impose a circadian pattern of expression on a number of clock-controlled genes.
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.
RORγt is the transcription factor is essential for lymphoid organogenesis in the embryo, in particular lymph nodes and Peyer’s patches, but not the spleen.
RORγt is the transcription factor is essential for the specific immune cells responsible for embryonic lymphoid formation, the Lymphoid Tissue inducer (LTi) cells.
Within these cells, retinoic acid induces expression of RORc.
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.
RORγt also plays a role in inhibiting apoptosis of undifferentiated T cells and promoting their differentiation into Th17 cells.
RORγ is expressed in certain subsets of cancer stem cells in pancreatic cancer and shows a strong correlation with tumor stage and lymph node invasion.
Amplification of the RORC gene has also been observed in malignancies such as lung, breast and neuroendocrine prostate cancer, as well.
Intermediates within the cholesterol pathway have been shown to activate RORγt.
As antagonism of the RORγ receptor may have therapeutic applications in the treatment of inflammatory diseases,and may allow the immune system to combat cancer.