RAR-related orphan receptor alpha (RORα), also known asNR1F1 (nuclear receptor subfamily 1, group F, member 1) is anuclear receptor that in humans is encoded by theRORAgene.[5] RORα participates in the transcriptional regulation of some genes involved incircadian rhythm.[6] In mice, RORα is essential for development ofcerebellum[7][8] through direct regulation of genes expressed in Purkinje cells.[9] It also plays an essential role in the development oftype 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient.[10][11] In addition, although present in normal numbers, theILC3 and Th17 cells from RORα deficient mice are defective forcytokine production.[12]
The first three-human isoforms of RORα were initiallycloned 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 theliver,kidney,retina, andlung.[14] Of interest, it was around this time that RORα abundance was found to be circadian in the mammaliansuprachiasmatic nucleus.[15] RORα is necessary for normalcircadian rhythms inmice,[16] demonstrating its importance inchronobiology.
The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors.[16] In humans, 4isoforms of RORα have been identified, which are generated via alternativesplicing andpromoter usage, and exhibit differential tissue-specific expression. Theprotein structure of RORα consists of four canonical functional groups: anN-terminal (A/B) domain, aDNA-bindingdomain containing twozinc fingers, a hinge domain, and aC-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 oftranscriptional activity.[5]
The coremammalian circadian clock is anegative feedback loop which consists ofPer1/Per2,Cry1/Cry2,Bmal1, andClock.[15] This feedback loop is stabilized through another loop involving the transcriptional regulation ofBmal1.[17]Transactivation ofBmal1 is regulated through the upstream ROR/REV-ERBResponse Element (RRE) in theBmal1 promoter, to which RORα andREV-ERBα bind.[17] This stabilizing regulatory loop itself is induced by the Bmal1/Clockheterodimer, which induces transcription ofRORα andREV-ERBα.[15] RORα, which activates transcription ofBmal1, and REV-ERBα, which represses transcription ofBmal1, compete to bind to the RRE.[17] This feedback loop regulating the expression ofBmal1 is thought to stabilize the core clock mechanism, helping to buffer it against changes in theenvironment.[17]
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]
RORα,RORβ, andRORγ 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, andlymphocyte 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 inCentral Nervous System (CNS) tissues involved in processing sensory information and in generatingcircadian rhythms while RORγ is critical inlymph nodeorganogenesis andthymopoeisis.[20]
The DNA-binding domains of the DHR3 orphan receptor inDrosophila shows especially closehomology withinamino andcarboxy regions adjacent to the second zinc finger region in RORα, suggesting that this group ofresidues is important for the proteins' functionalities.[5]
PDP1 and VRI inDrosophila 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 afeedback 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.
Humancytochrome 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 thesense 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), andGRIP-1 physically interact with RORα.[14]
LXXLL motif: ROR interacts with SRC-1, GRIP-l, CBP, and p300 via theLXXLL (L=Leucine, X=any amino acid) motifs on these proteins.[14]
Ubiquitination: RORα is targeted for theproteasome by ubiquitination. Aco-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 regulatemetabolism,development,immunity, and circadian rhythm, they show potential asdrug targets. Synthetic ligands have a variety of potential therapeutic uses, and can be used to treat diseases such asdiabetes,atherosclerosis,autoimmunity, andcancer. T0901317 and SR1001, two synthetic ligands, have been found to be RORα andRORγinverse agonists that suppressreporter activity and have been shown to delay onset and clinical severity ofmultiple sclerosis and otherTh17 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 treatobesity and diabetes as well as cancer of thebreast,ovaries, andprostate. 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.Bibcode:1996BBRC..227...82P.doi:10.1006/bbrc.1996.1471.PMID8858107.
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.Bibcode:1993BBRC..194.1371B.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.Bibcode:1996BBRC..227...82P.doi:10.1006/bbrc.1996.1471.PMID8858107.
Gawlas K, Stunnenberg HG (December 2000). "Differential binding and transcriptional behaviour of two highly related orphan receptors, ROR alpha(4) and ROR beta(1)".Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression.1494 (3):236–41.doi:10.1016/s0167-4781(00)00237-2.PMID11121580.
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.
