P51450 (RORG_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 131. History...
Names and origin
|Protein names||Recommended name:|
Nuclear receptor ROR-gamma
Nuclear receptor RZR-gamma
Nuclear receptor subfamily 1 group F member 3
RAR-related orphan receptor C
Retinoid-related orphan receptor-gamma
Thymus orphan receptor
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||516 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 cellular differentiation, immunity, peripheral 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 gene regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates the circadian expression of clock genes such as CRY1, ARNTL/BMAL1 and NR1D1 in peripheral tissues and in a tissue-selective manner. 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 RORC-mediated activation of the expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Involved in the regulation of the rhythmic expression of genes involved in glucose and lipid metabolism, including PLIN2 and AVPR1A. Negative regulator of adipocyte differentiation through the regulation of early phase genes expression, such as MMP3. Controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. In liver, has specific and redundant functions with RORA 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 SULT1E1. Also plays also a role in the regulation of hepatocyte glucose metabolism through the regulation of G6PC and PCK1. Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.17
Isoform 2:Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes and Peyer's patches (Ref.5, Ref.7, Ref.8). Required for the generation of LTi (lymphoid tissue inducer) cells. Regulates thymocyte survival through DNA-binding on ROREs of target gene promoter regions and recruitment of coactivaros via the AF-2. Also plays a key role, downstream of IL6 and TGFB and synergistically with RORA, for 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. May also play a role in the pre-TCR activation cascade leading to the maturation of alpha/beta T-cells and may participate in the regulation of DNA accessibility in the TCR-J(alpha) locus. Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.14 Ref.15 Ref.17
Interacts (via AF-2 motif) with the coactivators NCOA1, NCOA2 and PPARGC1A (via LXXLL motif). Interacts with the corepressor NCOR1.
Isoform 1 is widely expressed with highest levels in muscle, kidney and liver. Isoform 2 is expressed primarily in immature thymocytes and the subset of mature T(H)17 cells. Neither isoform isexpressed in spleen or bone marrow. Ref.4 Ref.5 Ref.7 Ref.9 Ref.11 Ref.12 Ref.17
In 3T3-L1 cells, sharp decline at mRNA and protein levels upon induction of adipocyte differentiation. Isoform 2 is detected in the immediate vicinity of vessels among small clusters of CD45+ cells as early as E12.5. At E16.5, isoform 2 is expressed exclusively in tight clusters of cells found in lymph node anlagen, in the submucosal region of the intestine and around central vessels in the spleen. Ref.7 Ref.11 Ref.15
Isoform 1 expression oscillates diurnally in peripheral tissues such as liver, brown adipose tissue (BAT), kidney and small intestines. Isoform 2 is induced upon antigen receptor ligation in the presence of IL6 and TGB1 (via STAT3). Ref.9 Ref.12 Ref.17
Mice show decreased adipocytes size and highly insulin sensitivity, leading to an improved control of circulating fatty acids. Mutants are protected from hyperglycemia and insulin resistance in the state of obesity. Loss of circadian pattern of some clock genes expression in the peripheral tissues and massive apoptosis of thymocytes. Knockout mice for isoform 2 lack all lymph nodes and Peyer's patches, as well as LTi cells. They also show a reduction of T(H)17 cells in the lamina propria by at least 10-fold to less than 1% of the T(H) cells. Mice are less susceptible to autoimmune inflammatory diseases. Ref.7 Ref.8 Ref.9 Ref.11 Ref.15 Ref.17
Contains 1 nuclear receptor DNA-binding domain.
|This entry describes 2 isoforms produced by alternative promoter usage. [Align] [Select]|
|Isoform 1 (identifier: P51450-1) |
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: P51450-2) |
Also known as: RORgT;
The sequence of this isoform differs from the canonical sequence as follows:
22-24: HTS → MRT
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 516||516||Nuclear receptor ROR-gamma||PRO_0000053518|
|DNA binding||31 – 96||66||Nuclear receptor Ref.8 Ref.17|
|Zinc finger||31 – 51||21||NR C4-type|
|Zinc finger||67 – 91||25||NR C4-type|
|Region||1 – 30||30||Modulating Potential|
|Region||97 – 266||170||Hinge Potential|
|Region||267 – 516||250||Ligand-binding Potential|
|Motif||499 – 504||6||AF-2|
|Compositional bias||119 – 130||12||Poly-Gln|
|Alternative sequence||1 – 21||21||Missing in isoform 2.||VSP_003659|
|Alternative sequence||22 – 24||3||HTS → MRT in isoform 2.||VSP_003660|
|Mutagenesis||31||1||C → A: Loss of adipogenesis inhibition, when associated with A-48. Ref.15|
|Mutagenesis||48||1||C → A: Loss of adipogenesis inhibition, when associated with A-31. Ref.15|
|Mutagenesis||56 – 57||2||RR → AG: Abolishes DNA-binding. No effect neither on interaction with NCOA1 and NCOA2 nor on inhibition of NFATC1 expression.|
|Mutagenesis||500||1||Y → F: Abolishes interaction with NCOA1 and NCOA2. Ref.8|
|Mutagenesis||502||1||E → Q: Loss of transactivation function. Ref.17|
|Sequence conflict||181||1||G → D in AAB02582. Ref.3|
|Sequence conflict||352||1||T → K in AAB02582. Ref.3|
|Sequence conflict||352||1||T → K in AAD46913. Ref.4|
|Sequence conflict||352||1||T → K in AAH14804. Ref.6|
|||"Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element."|
Medvedev A., Yan Z.H., Hirose T., Giguere V., Jetten A.M.
Gene 181:199-206(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
|||"Genomic structure and chromosomal mapping of the nuclear orphan receptor ROR gamma (RORC) gene."|
Medvedev A., Chistokhina A., Hirose A., Jetten A.M.
Genomics 46:93-102(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
|||"TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals."|
Ortiz M.A., Piedrafita F.J., Pfahl M., Maki R.
Mol. Endocrinol. 9:1679-1691(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
|||"RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells."|
He Y.-W., Deftos M.L., Ojala E.W., Bevan M.J.
Immunity 9:797-806(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION IN T CELLS, TISSUE SPECIFICITY.
|||"RORgammaT, a thymus-specific isoform of the orphan nuclear receptor RORg/TOR, is up-regulated by signaling through the pre-T cell receptor (TCR) and binds to the TEA promoter."|
Villey I., De Chasseval R., De Villartay J.-P.
Eur. J. Immunol. 29:4072-4080(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION IN PRE-TCR ACTIVATION (ISOFORM 2), TISSUE SPECIFICITY.
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
|||"An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells."|
Eberl G., Marmon S., Sunshine M.J., Rennert P.D., Choi Y., Littman D.R.
Nat. Immunol. 5:64-73(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN THYMOPOIESIS (ISOFORM 2), DISRUPTION PHENOTYPE (ISOFORM 2), DEVELOPMENTAL STAGE (ISOFORM 2), TISSUE SPECIFICITY (ISOFORM 2).
|||"RORgammat recruits steroid receptor coactivators to ensure thymocyte survival."|
Xie H., Sadim M.S., Sun Z.
J. Immunol. 175:3800-3809(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN THYMOCYTE SURVIVAL (ISOFORM 2), INTERACTION WITH NCOA1 AND NCOA2, DISRUPTION PHENOTYPE, DNA-BINDING, MUTAGENESIS OF 56-ARG-ARG-57 AND TYR-500, DOMAIN.
|||"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells."|
Ivanov I.I., McKenzie B.S., Zhou L., Tadokoro C.E., Lepelley A., Lafaille J.J., Cua D.J., Littman D.R.
Cell 126:1121-1133(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN T(H)17 CELLS DIFFERENTIATION (ISOFORM 2), DISRUPTION PHENOTYPE (ISOFORM 2), INDUCTION BY IL6 AND TGFB1 (ISOFORM 2), TISSUE SPECIFICITY (ISOFORM 2).
|||"Transcriptional coactivator PGC-1alpha integrates the mammalian clock and energy metabolism."|
Liu C., Li S., Liu T., Borjigin J., Lin J.D.
Nature 447:477-481(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PPARGC1A.
|||"Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism."|
Kang H.S., Angers M., Beak J.Y., Wu X., Gimble J.M., Wada T., Xie W., Collins J.B., Grissom S.F., Jetten A.M.
Physiol. Genomics 31:281-294(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN METABOLISM REGULATION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
|||"T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma."|
Yang X.O., Pappu B.P., Nurieva R., Akimzhanov A., Kang H.S., Chung Y., Ma L., Shah B., Panopoulos A.D., Schluns K.S., Watowich S.S., Tian Q., Jetten A.M., Dong C.
Immunity 28:29-39(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN T(H)17 CELLS DIFFERENTIATION (ISOFORM 2), INDUCTION BY IL6 AND TGB1 (ISOFORM 2), TISSUE SPECIFICITY (ISOFORM 2).
|||"Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism."|
Nucl. Recept. Signal. 7:3-35(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands."|
Wang Y., Kumar N., Solt L.A., Richardson T.I., Helvering L.M., Crumbley C., Garcia-Ordonez R.D., Stayrook K.R., Zhang X., Novick S., Chalmers M.J., Griffin P.R., Burris T.P.
J. Biol. Chem. 285:5013-5025(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN GLUCOSE METABOLISM REGULATION, IDENTIFICATION OF LIGANDS.
|||"Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma."|
Meissburger B., Ukropec J., Roeder E., Beaton N., Geiger M., Teupser D., Civan B., Langhans W., Nawroth P.P., Gasperikova D., Rudofsky G., Wolfrum C.
EMBO Mol. Med. 3:637-651(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ADIPOGENESIS, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, MUTAGENESIS OF CYS-31 AND CYS-48.
|||"Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand."|
Solt L.A., Kumar N., Nuhant P., Wang Y., Lauer J.L., Liu J., Istrate M.A., Kamenecka T.M., Roush W.R., Vidovic D., Schuerer S.C., Xu J., Wagoner G., Drew P.D., Griffin P.R., Burris T.P.
Nature 472:491-494(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NCOR1 AND NCOA2, IDENTIFICATION OF LIGANDS.
|||"RORgamma directly regulates the circadian expression of clock genes and downstream targets in vivo."|
Takeda Y., Jothi R., Birault V., Jetten A.M.
Nucleic Acids Res. 40:8519-8535(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CIRCADIAN RHYTHMS, TISSUE SPECIFICITY, INDUCTION, SUBCELLULAR LOCATION, DNA-BINDING, DISRUPTION PHENOTYPE, MUTAGENESIS OF GLU-502.
|||"Action of RORs and their ligands in (patho)physiology."|
Solt L.A., Burris T.P.
Trends Endocrinol. Metab. 23:619-627(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION AND LIGANDS.
|+||Additional computationally mapped references.|
|U43508 mRNA. Translation: AAB40709.1.|
AF019660 AF019659 Genomic DNA. Translation: AAC53501.1.
U39071 mRNA. Translation: AAB02582.1.
AF163668 mRNA. Translation: AAD46913.1.
AJ132394 mRNA. Translation: CAA10661.1.
BC014804 mRNA. Translation: AAH14804.1.
|RefSeq||NP_035411.2. NM_011281.2. |
3D structure databases
|SMR||P51450. Positions 29-505. |
Protein-protein interaction databases
|BioGrid||202957. 3 interactions.|
|IntAct||P51450. 2 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000029795; ENSMUSP00000029795; ENSMUSG00000028150. |
ENSMUST00000107292; ENSMUSP00000102913; ENSMUSG00000028150.
|UCSC||uc008qfy.2. mouse. [P51450-1]|
|MGI||MGI:104856. Rorc. |
Gene expression databases
Family and domain databases
|Gene3D||1.10.565.10. 2 hits. |
22.214.171.124. 1 hit.
|InterPro||IPR008946. Nucl_hormone_rcpt_ligand-bd. |
|Pfam||PF00104. Hormone_recep. 1 hit. |
PF00105. zf-C4. 1 hit.
|PRINTS||PR01293. RORNUCRECPTR. |
|SMART||SM00430. HOLI. 1 hit. |
SM00399. ZnF_C4. 1 hit.
|SUPFAM||SSF48508. SSF48508. 1 hit. |
|PROSITE||PS00031. NUCLEAR_REC_DBD_1. 1 hit. |
PS51030. NUCLEAR_REC_DBD_2. 1 hit.
|Accession||Primary (citable) accession number: P51450|
Secondary accession number(s): Q61027 Q9R177
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|