RAR-related orphan receptor gamma
Encyclopedia
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 member of the nuclear receptor
family of transcription factor
s.
are produced from the same RORC gene, probably by selection of alternative promoters.
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
.
where it is expressed exclusively in immature CD4
+/CD8
+ thymocyte
s and in lymphoid tissue inducer (LTi) cells. RORγt inhibitors are under development for autoimmune diseases.
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.
The best studied aspect of RORγ function (arising from the RORγt isoform) is in the immune system
. First, it is essential for lymphoid organogenesis, in particular lymph node
s and Peyer's patches, but not the spleen
. Second, it plays an important regulatory role in thymopoiesis, more particularly by reducing apoptosis
of thymocyte
s and promoting thymocyte differentiation into pro-inflammatory T helper 17
(Th17) cells. The mechanism of inhibition of apoptosis and differentiation into Th17 cells may be due to down regulation by RORγt of the expression of Fas ligand
and IL2
respectively.
The other isoform, RORγ, appears to be involved in the regulation of circadian rhythm
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
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the RORC (RAR
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
-related orphan receptor C) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. RORγ is member of the nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
family of transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s.
Gene expression
Two isoformsProtein isoform
A protein isoform is any of several different forms of the same protein. Different forms of a protein may be produced from related genes, or may arise from the same gene by alternative splicing. A large number of isoforms are caused by single-nucleotide polymorphisms or SNPs, small genetic...
are produced from the same RORC gene, probably by selection of alternative promoters.
- RORγ (also referred to as RORγ1) – produced from an mRNA containing exonExonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
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.
RORγ
The mRNA 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 phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s identified in RORγ-/- knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
(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
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
fashion (e.g., in the liver and kidney) or constitutively (e.g., in the muscle).
In contrast to other ROR genes
RAR-related orphan receptor
The RAR-related orphan receptors are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene...
, the RORC gene is not expressed in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
RORγt
The tissue distribution of the second isoform, RORγt, appears to be highly restricted to the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
where it is expressed exclusively in immature CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
+/CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
+ thymocyte
Thymocyte
Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which...
s and in lymphoid tissue inducer (LTi) cells. RORγt inhibitors are under development for autoimmune diseases.
Function
The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear receptorNuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
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.
The best studied aspect of RORγ function (arising from the RORγt isoform) is in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. First, it is essential for lymphoid organogenesis, in particular lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s and Peyer's patches, but not the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
. Second, it plays an important regulatory role in thymopoiesis, more particularly by reducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of thymocyte
Thymocyte
Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes . The thymus provides an inductive environment, which...
s and promoting thymocyte differentiation into pro-inflammatory T helper 17
T helper 17 cell
T helper 17 cells are a subset of T helper cells producing interleukin 17 discovered in 2007. They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease such as multiple sclerosis , but also...
(Th17) cells. The mechanism of inhibition of apoptosis and differentiation into Th17 cells may be due to down regulation by RORγt of the expression of Fas ligand
FAS ligand
Fas ligand is a type-II transmembrane protein that belongs to the tumor necrosis factor family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.- Structure :Fas ligand or...
and IL2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
respectively.
The other isoform, RORγ, appears to be involved in the regulation of circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
s. This protein can bind to and activate the promoter of the ARNTL (BMAL1)
ARNTL
Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene which is associated with susceptibility to hypertension and type 2 diabetes.-Function:...
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
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
.