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, respo ...

that in humans is encoded by the ''RORC'' (

RAR RAR or Rar may refer to: * Radio acoustic ranging, a non-visual technique for determining a ship's position at sea * "rar", the ISO 639-2 code for the Cook Islands Māori language * RAR (file format), a proprietary compressed archive file format in ...

-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 ba ...

. RORγ is a member of the

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

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 fu ...

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 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...

cells) and it also regulates circadian rhythms. 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 isof ...

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 Protein biosynthesis, synthesizing a protein. mRNA is ...

containing

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

s 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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

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 proper ...

s identified in RORγ-/-

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

(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 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 ...

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 par ...

RORγt

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

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ...

⁺/ CD8⁺ thymocytes, T helper 17 (

) cells and in type 3 innate lymphoid cells (

ILC3 Type 3 innate lymphoid cells (ILC3) are immune 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-commensal mutualis ...

). 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 involv ...

Function

The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of

s. 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 rhythm 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., Endogeny (biology), endogeno ...

s. 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 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...

. 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 splinte ...

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

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

s and Peyer's patches, 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

of thymocytes and promoting thymocyte differentiation into pro-inflammatory

T helper 17 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg different ...

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

oxazolone Oxazolone is a chemical compound and functional group, with the molecular formula C3H3NO2. It was named in-line with the Hantzsch–Widman nomenclature and is part of a large family of oxazole based compounds. There are a total of 5 structural iso ...

-induced colitis.

Cancer

RORγ is expressed in certain subsets of cancer stem cells ( EpCAM+/

MSI2 Musashi-2, also known as Musashi RNA binding protein 2, is a protein that in humans is encoded by the ''MSI2'' gene. Like its homologue musashi-1 (''MSI1''), it is an RNA-binding protein involved in stemness. Expression There are two homolog ...

+) in

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...

and shows a strong correlation with tumor stage and

invasion. Amplification of the ''RORC'' gene has also been observed in other malignancies such as

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

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 secret ...

and neuroendocrine

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

Ligands

Various oxysterols and in particular the cholesterol percursor

desmosterol Desmosterol is a molecule similar to cholesterol. Desmosterol is the immediate precursor of cholesterol in the Bloch pathway of cholesterol biosynthesis. 24-dehydrocholesterol reductase catalyses the reduction of desmosterol to cholesterol. It i ...

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