InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Rora

Summary

InnateDB Protein

IDBP-181480.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Rora

Protein Name

RAR-related orphan receptor alpha

Synonyms

9530021D13Rik; nmf267; Nr1f1; ROR1; ROR2; ROR3; sg; staggerer; tmgc26;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000034766

InnateDB Gene

IDBG-181478 (Rora)

Protein Structure

UniProt Annotation

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, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium- mediated signal transduction. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/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 G6PC 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. {ECO:0000269PubMed:11053433, ECO:0000269PubMed:14687547, ECO:0000269PubMed:15821743, ECO:0000269PubMed:17666523, ECO:0000269PubMed:18055760, ECO:0000269PubMed:18164222, ECO:0000269PubMed:18441015, ECO:0000269PubMed:19014374, ECO:0000269PubMed:19324970, ECO:0000269PubMed:19965867, ECO:0000269PubMed:21499262, ECO:0000269PubMed:22753030, ECO:0000269PubMed:23172836}.

Subcellular Localization

Nucleus {ECO:0000255PROSITE- ProRule:PRU00407, ECO:0000269PubMed:22753030}.

Disease Associations

Note=Defects in Rora are the cause of the staggerer (SG) mutant phenotype which is characterized by disturbance of Purkinje cell development and immune system functioning. This phenotype exhibits lower body weight, reduced adiposity, decreased plasma cholesterol, triglyceride and apolipoprotein CIII levels, and is resistant to diet-induced obesity. Also has abnormal circadian rhythms.

Tissue Specificity

Expressed in cerebellum, heart, liver, lung, kidney, retina and brown and white adipose tissues. Expressed in the subset of mature Th17 cells. {ECO:0000269PubMed:17666523, ECO:0000269PubMed:18164222, ECO:0000269PubMed:18441015, ECO:0000269PubMed:22753030}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 8 experimentally validated interaction(s) in this database.
They are also associated with 25 interaction(s) predicted by orthology.

Experimentally validated
Total	8 [view]
Protein-Protein	6 [view]
Protein-DNA	1 [view]
Protein-RNA	1 [view]
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	25 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001222	transcription corepressor binding
GO:0001223	transcription coactivator binding
GO:0003677	DNA binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0003707	steroid hormone receptor activity
GO:0004879	ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity
GO:0005515	protein binding
GO:0008013	beta-catenin binding
GO:0008134	transcription factor binding
GO:0008142	oxysterol binding
GO:0008270	zinc ion binding
GO:0043565	sequence-specific DNA binding
GO:0098531	direct ligand regulated sequence-specific DNA binding transcription factor activity

Biological Process

GO:0001525	angiogenesis
GO:0006351	transcription, DNA-templated
GO:0006355	regulation of transcription, DNA-templated
GO:0006805	xenobiotic metabolic process
GO:0006809	nitric oxide biosynthetic process
GO:0007623	circadian rhythm
GO:0008589	regulation of smoothened signaling pathway
GO:0010575	positive regulation vascular endothelial growth factor production
GO:0010906	regulation of glucose metabolic process
GO:0019218	regulation of steroid metabolic process
GO:0021702	cerebellar Purkinje cell differentiation
GO:0021930	cerebellar granule cell precursor proliferation
GO:0030522	intracellular receptor signaling pathway
GO:0032922	circadian regulation of gene expression
GO:0036315	cellular response to sterol
GO:0042692	muscle cell differentiation
GO:0042752	regulation of circadian rhythm
GO:0042753	positive regulation of circadian rhythm
GO:0043030	regulation of macrophage activation
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043401	steroid hormone mediated signaling pathway
GO:0045087	innate immune response (InnateDB)
GO:0045599	negative regulation of fat cell differentiation
GO:0045893	positive regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046068	cGMP metabolic process
GO:0050728	negative regulation of inflammatory response
GO:0060850	regulation of transcription involved in cell fate commitment
GO:0070328	triglyceride homeostasis
GO:0071456	cellular response to hypoxia
GO:0072539	T-helper 17 cell differentiation
GO:2000188	regulation of cholesterol homeostasis

Cellular Component

GO:0005634	nucleus
GO:0005654	nucleoplasm

Protein Structure and Domains

PDB ID

MGI:104661

InterPro

IPR000536 Nuclear hormone receptor, ligand-binding, core
IPR001628 Zinc finger, nuclear hormone receptor-type
IPR001723 Steroid hormone receptor
IPR001728 Thyroid hormone receptor
IPR003079 Nuclear receptor ROR
IPR008946 Nuclear hormone receptor, ligand-binding

PFAM

PF00104
PF00105

PRINTS

PR00047
PR00398
PR00546
PR01293

PIRSF

SMART

SM00430
SM00399

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt