Recombinant Human Nuclear receptor ROR-alpha (RORA)

Function

Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development (PubMed:29656859). Regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC1 and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling

Subcellular Location

Nucleus

Disease Association

Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (IDDECA) : An autosomal dominant neurodevelopmental disorder that manifests with variable features of mild-to-severe intellectual disability, developmental delay, autism spectrum disorder, cerebellar ataxia and epilepsy. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed in a number of tissues. Expressed in both regulatory T-cells (Treg) and effector T-cells (Teff) (PubMed:18354202, PubMed:7916608). Isoform 4: Highly expressed in the central nervous system, including in the cerebellum (PubMed:29656859)

Subunit

Monomer. Interacts (via the DNA-binding domain) with HIF1A; the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interacts with CEBPB; the interaction disrupts the interaction CEBPB:EP300. Interacts with the coactivators NCOA2, PPARGC1A (via LXXLL motif), EP300 and MED1. Interacts with the corepressor NCOR1. Interacts with MAGED1 and CTNNB1. Interacts with CRY1 and PER2. Interacts (via AF-2 motif) with PROX1 (By similarity). Interacts with NRIP1. Isoform 4 interacts (via AF-2 motif) with isoform 1 of FOXP3 (via LXXLL motif)

• Giguere V. et al. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. — Genes Dev. (1994)
• Becker-Andre M. et al. Identification of nuclear receptor mRNAs by RT-PCR amplification of conserved zinc-finger motif sequences. — Biochem. Biophys. Res. Commun. (1993)
• Kaighin V.A. et al. Isolation of cDNA coding for multiple human nuclear receptor clones. (DEC-)
• Zody M.C. et al. Analysis of the DNA sequence and duplication history of human chromosome 15. — Nature (2006)
• Mural R.J. et al. PubMed: CI-56FT96O07V0QG (JUL-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Harding H.P. et al. Transcriptional activation and repression by RORalpha, an orphan nuclear receptor required for cerebellar development. — Mol. Endocrinol. (1997)
• Atkins G.B. et al. Coactivators for the orphan nuclear receptor RORalpha. — Mol. Endocrinol. (1999)