RAR-related orphan receptor gamma (RORγ) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''RORC'' ( RAR-related orphan receptor C)

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. RORγ is a member of the nuclear receptor family of

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s. It is mainly expressed in

immune cells White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...

( Th17 cells) and it also regulates

circadian rhythms A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

. It may be involved in the progression of certain types of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

Gene expression

Two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

are produced from the same ''RORC'' gene, probably by selection of alternative promoters. * RORγ (also referred to as RORγ1) – produced from an

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

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.

RORγ

The

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

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

s 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 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). In contrast to other ROR genes, the RORC gene is not expressed in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

RORγt

The second isoform, RORγt, is expressed in various immune cells. Of those, the most prominent examples are immature CD4⁺/

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...

⁺

thymocyte A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymo ...

s, T helper 17 ( Th17) cells and in type 3 innate lymphoid cells (

ILC3 Type 3 innate lymphoid cells (ILC3) are immune Cell (biology), cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-co ...

). 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. RORγt inhibitors are under development for the treatment of autoimmune diseases such as

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

and

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

Function

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.

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, 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. 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.

Immune regulation

RORγt is the most studied of the two isoforms. Its best understood functionality is in the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

. The transcription factor is essential for lymphoid organogenesis, in particular lymph nodes and

Peyer's patches Peyer's patches (or aggregated lymphoid nodules) are organized lymphoid follicles, named after the 17th-century Swiss anatomist Johann Conrad Peyer. * Reprinted as: * Peyer referred to Peyer's patches as ''plexus'' or ''agmina glandularum'' (c ...

, but not the

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

. RORγt also plays an important regulatory role in thymopoiesis, by reducing apoptosis of

s 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 T_reg cell subpopulation in the colon, and is induced by symbiotic

microflora Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found to ...

. Abrogation of the gene's activity generally increases type 2 cytokines and may make mice more vulnerable to oxazolone-induced

colitis Colitis is swelling or inflammation of the large intestine ( colon). Colitis may be acute and self-limited or long-term. It broadly fits into the category of digestive diseases. In a medical context, the label ''colitis'' (without qualification ...

Cancer

RORγ is expressed in certain subsets of

cancer stem cells Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sampl ...

(

EpCAM Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, prol ...

+/ MSI2+) 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 other malignancies such as lung,

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

and neuroendocrine prostate cancer.

Ligands

Various

oxysterol An oxysterol is a derivative of cholesterol obtained by oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, fatty ...

s and in particular the cholesterol percursor desmosterol is claimed to be the endogenous activator of RORγ.

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. 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.

References

External links

* {{Receptor/signaling modulators Intracellular receptors Transcription factors