RAR-related orphan receptor-γ

Nomenclature: RAR-related orphan receptor-γ

Systematic Nomenclature: NR1F3

Family: 1F. Retinoic acid-related orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 518 1q21 RORC RAR-related orphan receptor C 4
Mouse 516 3F2 Rorc RAR-related orphan receptor gamma 9
Rat - 2q34 Rorc RAR-related orphan receptor C
Previous and Unofficial Names
RZRG
RORG
TOR
RORγ
RZRγ
NR1F3
LOC368158
MGC189525
RAR-related orphan receptor C
RAR-related orphan receptor gamma
nuclear receptor ROR-gamma
thymus orphan receptor
Thor
RORgamma
nuclear receptor RZR-gamma
similar to Nuclear receptor ROR-gamma
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Ligand binding domain of RORgamma in complex with endogenous ligand
PDB Id:  3L0L
Ligand:  25-hydroxycholesterol   This ligand is endogenous
Resolution:  1.74Å
Species:  Human
References:  5
Natural/Endogenous Ligands
Comments: Orphan
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
25-hydroxycholesterol Hs Agonist - - 5
[5]
Agonist Comments
Even though no ligands have been identified, hydroxycholesterols have been shown to promote the recruitment of coactivators by RORgamma using biochemical assays. [5]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
tretinoin Hs Antagonist - - 10
[10]
ALRT 1550 Hs Antagonist - - 10
[10]
Antagonist Comments
Both ALRT 1550 and all-trans retinoic acid partially inhibit RORg transcriptional activity.
DNA Binding
Structure:  Homodimer
HRE core sequence:  AGGTCA nnnnn AGGTCA
Response element:  DR4, DR5, Half site
DNA Binding Comments
It has been shown that mouse RORγ does not recognise the classical ROREs but binds with high affinity as a homodimer to DR4 and DR5 elements.
Co-binding Partners
Name Interaction Effect Reference
Mi-2beta Physical, Functional Mi-2beta: A yeast two-hybrid screen with Y190 yeast cells under stringent conditions resulted in the identification of CHD4, also known as Mi-2beta, as a RORgamma-interacting protein. This interaction was confirmed by GST pull-down assays. This interaction occurred within the middle regulatory region (amino acids 719-1164) of Mi-2beta. Transfection of Gal4-RORgamma into HeLa cells resulted in constitutive transactivation of the MH100-tk-luc reporter. The addition of Mi-2beta resulted in a dramatic 50% decrease in Gal4-RORgamma-mediated transactivation. These data demonstrate that RORgamma forms a protein-protein interaction with the regulatory region of Mi-2beta, resulting in inhibition of RORgamma transcriptional activity . 6
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
NCOA1 Co-activator No No Yes 7
HR Co-repressor No Yes Yes 8
Tissue Distribution
Muscle, thymus, testis, pancreas, prostate, heart and liver
Expression level:  High
Species:  Human
Technique:  in situ hybridization, Immunohistology, Northern Blot, other
References:  1-2,4,9
Tissue Distribution Comments
In the human tissues RORγ was shown to be highly expressed as a 3.2 kb mRNA. In thymus, two other transcripts at 7.2 and 5.2 kb were also detected. In mouse, other authors found a predominant expression in thymus as in other tissues such as liver, heart, tongue, muscle, and diaphragm. Notably, no expression was found in spleen, or bone marrow. The major transcript is found at 2.5 kb but a 3.5 kb form is detected in several organs such as thymus. The same study report the expression in a number of mammalian cell lines. Recently, it has been shown that during fetal life, the nuclear hormone receptor RORgamma(t) is expressed exclusively in and is required for the generation of lymphoid tissue inducer cells.
Physiological Consequences of Altering Gene Expression
ROR gamma null mice: Homozygotes for targeted null mutations exhibit lack of peripheral and mesenteric lymph nodes and Peyer's patches, reduced numbers of thymocytes, and increased apoptosis with loss of thymic expression of anti-apoptosic factor Bcl-xL
Species:  Mouse
Tissue:  Various
Technique:  Gene knockout
References:  11
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0008400 abnormal CD4-positive, alpha-beta intraepithelial T cell morphology PMID: 15247480 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0008401 abnormal CD8 positive, alpha-beta intraepithelial T cell morphology PMID: 15247480 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0000495 abnormal colon morphology PMID: 20226692 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002378 abnormal gut-associated lymphoid tissue morphology PMID: 14691482  15247480 
Ltatm1Dch|Rorc+|Rorctm2Litt Ltatm1Dch/Ltatm1Dch,Rorctm2Litt/Rorc+
involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
MGI:104797  MGI:104856  MP:0002378 abnormal gut-associated lymphoid tissue morphology PMID: 15247480 
Id2tm1Yyk|Rorc+|Rorctm2Litt Id2tm1Yyk/Id2tm1Yyk,Rorctm2Litt/Rorc+
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ
MGI:104856  MGI:96397  MP:0002378 abnormal gut-associated lymphoid tissue morphology PMID: 14691482 
Id2tm1Yyk|Rorc+|Rorctm2Litt Id2tm1Yyk/Id2tm1Yyk,Rorctm2Litt/Rorc+
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ
MGI:104856  MGI:96397  MP:0000716 abnormal immune system cell morphology PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0008751 abnormal interleukin level PMID: 17581589 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002450 abnormal lymph organ development PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0002450 abnormal lymph organ development PMID: 10963675 
Id2tm1Yyk|Rorc+|Rorctm2Litt Id2tm1Yyk/Id2tm1Yyk,Rorctm2Litt/Rorc+
involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ
MGI:104856  MGI:96397  MP:0002450 abnormal lymph organ development PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0008826 abnormal splenic cell ratio PMID: 10963675 
Rorctm1Litt|Tcra-Jtm3Krg Rorctm1Litt/Rorctm1Litt,Tcra-Jtm3Krg/Tcra-Jtm3Krg
involves: 129P2/OlaHsd * 129S6/SvEvTac
MGI:104856  MGI:98555  MP:0002145 abnormal T cell differentiation PMID: 17882258 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002145 abnormal T cell differentiation PMID: 17882258 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0002444 abnormal T cell physiology PMID: 10963675 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0008024 absent lymph nodes PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0008024 absent lymph nodes PMID: 10963675 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002831 absent Peyer's patches PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0002831 absent Peyer's patches PMID: 10963675 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002816 colitis PMID: 20226692 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0001652 colonic necrosis PMID: 20226692 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0008075 decreased CD4-positive T cell number PMID: 10963675 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0008079 decreased CD8-positive T cell number PMID: 10963675 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0005089 decreased double-negative T cell number PMID: 15247480 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0005092 decreased double-positive T cell number PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0005092 decreased double-positive T cell number PMID: 10963675 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0008045 decreased NK cell number PMID: 19084435 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0005018 decreased T cell number PMID: 10963675 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0004956 decreased thymus weight PMID: 10963675 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0000691 enlarged spleen PMID: 10963675 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0005090 increased double-negative T cell number PMID: 10963675 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0002412 increased susceptibility to bacterial infection PMID: 20226692 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0009788 increased susceptibility to bacterial infection induced morbidity/mortality PMID: 20226692 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0006413 increased T cell apoptosis PMID: 10963675 
Rorctm2Litt Rorctm2Litt/Rorctm2Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0009541 increased thymocyte apoptosis PMID: 14691482 
Rorctm1Amj Rorctm1Amj/Rorctm1Amj
either: (involves: 129/Sv * C57BL/6) or (involves: 129/Sv * C57BL/6 * DBA/2)
MGI:104856  MP:0001823 thymus hypoplasia PMID: 10963675 
Rorctm1Litt Rorctm1Litt/Rorctm1Litt
involves: 129P2/OlaHsd
MGI:104856  MP:0001263 weight loss PMID: 20226692 
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  nuclear receptor ROR-gamma isoform b (ROR gamma b): - This variant differs in the 5' UTR and coding region compared to canonical ROR gamma. It is shorter and has a distinct N-terminus compared to isoform a.
Amino acids:  497
Protein accession: 
References:  3

References

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1. Eberl G, Littman DR. (2003) The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol. Rev.195: 81-90. [PMID:12969312]

2. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. (2004) An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol.5 (1): 64-73. [PMID:14691482]

3. He YW, Deftos ML, Ojala EW, Bevan MJ. (1998) RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. Immunity9 (6): 797-806. [PMID:9881970]

4. Hirose T, Smith RJ, Jetten AM. (1994) ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochem. Biophys. Res. Commun.205 (3): 1976-83. [PMID:7811290]

5. Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y. (2010) Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol. Endocrinol.24 (5): 923-9. [PMID:20203100]

6. Johnson DR, Lovett JM, Hirsch M, Xia F, Chen JD. (2004) NuRD complex component Mi-2beta binds to and represses RORgamma-mediated transcriptional activation. Biochem. Biophys. Res. Commun.318 (3): 714-8. [PMID:15144897]

7. Kurebayashi S, Nakajima T, Kim SC, Chang CY, McDonnell DP, Renaud JP, Jetten AM. (2004) Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma. Biochem. Biophys. Res. Commun.315 (4): 919-27. [PMID:14985100]

8. Moraitis AN, Giguère V, Thompson CC. (2002) Novel mechanism of nuclear receptor corepressor interaction dictated by activation function 2 helix determinants. Mol. Cell. Biol.22 (19): 6831-41. [PMID:12215540]

9. Ortiz MA, Piedrafita FJ, Pfahl M, Maki R. (1995) TOR: a new orphan receptor expressed in the thymus that can modulate retinoid and thyroid hormone signals. Mol. Endocrinol.9 (12): 1679-91. [PMID:8614404]

10. Stehlin-Gaon C, Willmann D, Zeyer D, Sanglier S, Van Dorsselaer A, Renaud JP, Moras D, Schüle R. (2003) All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta. Nat. Struct. Biol.10 (10): 820-5. [PMID:12958591]

11. Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A, Brenner-Morton S, Mebius RE, Littman DR. (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science288 (5475): 2369-73. [PMID:10875923]

How to cite this page

1F. Retinoic acid-related orphans: RAR-related orphan receptor-γ. Last modified on 13/12/2013. Accessed on 01/11/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=600.