RAR-related orphan receptor alpha (RORα), also known as NR1F1 (nuclear receptor subfamily 1, group F, member 1) is a
nuclear receptor that in humans is encoded by the RORAgene.[5] RORα participates in the transcriptional regulation of some genes involved in
circadian rhythm.[6] In mice, RORα is essential for development of
cerebellum[7][8] through direct regulation of genes expressed in Purkinje cells.[9] It also plays an essential role in the development of
type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.[10][11] In addition, although present in normal numbers, the
ILC3 and Th17 cells from RORα deficient mice are defective for
cytokine production.[12]
Discovery
The first three-human isoforms of RORα were initially
cloned and characterized as nuclear receptors in 1994 by Giguère and colleagues, when their structure and function were first studied.[13]
In the early 2000s, various studies demonstrated that RORα displays rhythmic patterns of expression in a circadian cycle in the
liver,
kidney,
retina, and
lung.[14] Of interest, it was around this time that RORα abundance was found to be circadian in the mammalian
suprachiasmatic nucleus.[15] RORα is necessary for normal
circadian rhythms in
mice,[16] demonstrating its importance in
chronobiology.
Structure
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.[16] In humans, 4
isoforms of RORα have been identified, which are generated via alternative
splicing and
promoter usage, and exhibit differential tissue-specific expression. The
protein structure of RORα consists of four canonical functional groups: an
N-terminal (A/B) domain, a
DNA-binding
domain containing two
zinc fingers, a hinge domain, and a
C-terminalligand-binding domain. Within the ROR family, the DNA-binding domain is highly conserved, and the ligand-binding domain is only moderately conserved.[14] Different isoforms of RORα have different binding specificities and strengths of
transcriptional activity.[5]
Regulation of circadian rhythm
The core
mammalian circadian clock is a
negative feedback loop which consists of
Per1/Per2,
Cry1/Cry2,
Bmal1, and
Clock.[15] This feedback loop is stabilized through another loop involving the transcriptional regulation of Bmal1.[17]Transactivation of Bmal1 is regulated through the upstream ROR/REV-ERB
Response Element (RRE) in the Bmal1 promoter, to which RORα and
REV-ERBα bind.[17] This stabilizing regulatory loop itself is induced by the Bmal1/Clock
heterodimer, which induces transcription of RORα and REV-ERBα.[15] RORα, which activates transcription of Bmal1, and REV-ERBα, which represses transcription of Bmal1, compete to bind to the RRE.[17] This feedback loop regulating the expression of Bmal1 is thought to stabilize the core clock mechanism, helping to buffer it against changes in the
environment.[17]
Mechanism
Specific association with ROR elements (RORE) in regulatory regions is necessary for RORα's function as a transcriptional activator.[18] RORα achieves this by specific binding to a consensus core motif in RORE, RGGTCA. This interaction is possible through the association of RORα's first zinc finger with the core motif in the major groove, the P-box, and the association of its C-terminal extension with the AT-rich region in the 5’ region of RORE.[16]
Homology
RORα,
RORβ, and
RORγ are all transcriptional activators recognizing ROR-response elements.[19] ROR-alpha is expressed in a variety of cell types and is involved in regulating several aspects of development,
inflammatory responses, and
lymphocyte development.[20] The RORα isoforms (RORα1 through RORα3) arise via alternative RNA processing, with RORα2 and RORα3 sharing an amino-terminal region different from RORα1.[5] In contrast to RORα, RORβ is expressed in
Central Nervous System (CNS) tissues involved in processing sensory information and in generating
circadian rhythms while RORγ is critical in
lymph nodeorganogenesis and
thymopoeisis.[20]
The DNA-binding domains of the DHR3 orphan receptor in Drosophila shows especially close
homology within
amino and
carboxy regions adjacent to the second zinc finger region in RORα, suggesting that this group of
residues is important for the proteins' functionalities.[5]
PDP1 and VRI in Drosophila regulate circadian rhythm's by competing for the same binding site, the VP box, similarly to how ROR and REV-ERB competitively bind to RRE.[17] PDP1 and VRI constitute a
feedback loop and are functional homologs of ROR and REV-ERB in mammals.[17]
Direct orthologs of this gene have been identified in mice and humans.
Human
cytochrome c pseudogene HC2 and RORα share overlapping genomic organization with the HC2 pseudogene located within the RORα2 transcription unit. The nucleotide and deduced amino acid sequences of cytochrome c-processed pseudogene are on the
sense strand while those of the RORα2 amino-terminal exon are on the antisense strand.[5]
SRC-1,
CBP,
p300, TRIP-l,
TRIP-230, transcription intermediary protein-1 (
TIF-1), peroxisome proliferator-binding protein (PBP), and
GRIP-1 physically interact with RORα.[14]
LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via the
LXXLL (L=Leucine, X=any amino acid) motifs on these proteins.[14]
Ubiquitination: RORα is targeted for the
proteasome by ubiquitination. A
co-repressor, Hairless, stabilizes RORα by protecting it from this process, which also represses RORα.[21]
Sumoylation: UBE21/UBC9: Ubiquitin-conjugating enzyme I interacts with RORs, but its effect is not yet known.[16]
Because RORα and REV-ERBα are nuclear receptors that share the same target genes and are involved in processes that regulate
metabolism,
development,
immunity, and circadian rhythm, they show potential as
drug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such as
diabetes,
atherosclerosis,
autoimmunity, and
cancer. T0901317 and SR1001, two synthetic ligands, have been found to be RORα and
RORγinverse agonists that suppress
reporter activity and have been shown to delay onset and clinical severity of
multiple sclerosis and other
Th17 cell-mediated autoimmune diseases. SR1078 has been discovered as a RORα and RORγ agonist that increases the expression of G6PC and FGF21, yielding the therapeutic potential to treat
obesity and diabetes as well as cancer of the
breast,
ovaries, and
prostate. SR3335 has also been discovered as a RORα inverse agonist.[13]
^Paravicini G, Steinmayr M, André E, Becker-André M (October 1996). "The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily". Biochemical and Biophysical Research Communications. 227 (1): 82–7.
doi:
10.1006/bbrc.1996.1471.
PMID8858107.
Further reading
Giguère V, Beatty B, Squire J, Copeland NG, Jenkins NA (August 1995). "The orphan nuclear receptor ROR alpha (RORA) maps to a conserved region of homology on human chromosome 15q21-q22 and mouse chromosome 9". Genomics. 28 (3): 596–8.
doi:
10.1006/geno.1995.1197.
PMID7490103.
Becker-André M, André E, DeLamarter JF (August 1993). "Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences". Biochemical and Biophysical Research Communications. 194 (3): 1371–9.
doi:
10.1006/bbrc.1993.1976.
PMID7916608.
Paravicini G, Steinmayr M, André E, Becker-André M (October 1996). "The metastasis suppressor candidate nucleotide diphosphate kinase NM23 specifically interacts with members of the ROR/RZR nuclear orphan receptor subfamily". Biochemical and Biophysical Research Communications. 227 (1): 82–7.
doi:
10.1006/bbrc.1996.1471.
PMID8858107.
Moretti RM, Montagnani Marelli M, Motta M, Limonta P (2003). "Role of the orphan nuclear receptor ROR alpha in the control of the metastatic behavior of androgen-independent prostate cancer cells". Oncology Reports. 9 (5): 1139–43.
doi:
10.3892/or.9.5.1139.
PMID12168086.