RORC

Official Full Name

RAR related orphan receptor C

Organism

Homo sapiens

GeneID

6097

Background

The protein encoded by this gene is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear hormone receptors. The specific functions of this protein are not known; however, studies of a similar gene in mice have shown that this gene may be essential for lymphoid organogenesis and may play an important regulatory role in thymopoiesis. In addition, studies in mice suggest that the protein encoded by this gene may inhibit the expression of Fas ligand and IL2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

TOR; RORG; RZRG; IMD42; NR1F3; RZR-GAMMA;

Bio Chemical Class

Nuclear hormone receptor

Protein Sequence

MDRAPQRQHRASRELLAAKKTHTSQIEVIPCKICGDKSSGIHYGVITCEGCKGFFRRSQRCNAAYSCTRQQNCPIDRTSRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQRDSLHAEVQKQLQQRQQQQQEPVVKTPPAGAQGADTLTYTLGLPDGQLPLGSSPDLPEASACPPGLLKASGSGPSYSNNLAKAGLNGASCHLEYSPERGKAEGRESFYSTGSQLTPDRCGLRFEEHRHPGLGELGQGPDSYGSPSFRSTPEAPYASLTEIEHLVQSVCKSYRETCQLRLEDLLRQRSNIFSREEVTGYQRKSMWEMWERCAHHLTEAIQYVVEFAKRLSGFMELCQNDQIVLLKAGAMEVVLVRMCRAYNADNRTVFFEGKYGGMELFRALGCSELISSIFDFSHSLSALHFSEDEIALYTALVLINAHRPGLQEKRKVEQLQYNLELAFHHHLCKTHRQSILAKLPPKGKLRSLCSQHVERLQIFQHLHPIVVQAAFPPLYKELFSTETESPVGLSK

Open

Disease

Arterial occlusive disease, Autoimmune disease, Crohn disease, Liver cancer, Lung cancer, Multiple sclerosis, Psoriasis, Rheumatoid arthritis, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

16 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

The RORC gene, located on human chromosome 1q21.3, encodes a transcription factor belonging to the NR1F subfamily of the nuclear receptor superfamily. Through alternative promoter usage and exon splicing, the gene generates two major isoforms: RORγ1, comprising 518 amino acids, and RORγt, comprising 495 amino acids. Structurally, both isoforms share a DNA-binding domain (DBD) and a ligand-binding domain (LBD), but differ at the N-terminal region: RORγ1 contains a unique AF1 transactivation domain, whereas RORγt possesses a lymphocyte-specific sequence. This structural distinction underlies their tissue distribution and functional specificity: RORγ1 is broadly expressed in peripheral organs such as liver, muscle, and adipose tissue, while RORγt expression is restricted to immune cells (including Th17 cells, γδT cells, type 3 innate lymphoid cells) and thymic epithelial cells.

Figure 1. Schematic representation of RORγ structure. (Sun SL, et al., 2024)

Ligand-Dependent Transcriptional Regulation

As a ligand-dependent transcription factor, RORC regulates target genes by binding to ROR response elements (ROREs), which consist of a core 5'-AGGTCA-3' motif and an upstream AT-rich region. Under basal conditions, RORC recruits coactivators such as p300/CBP and PSF to maintain basal transcriptional activity. Endogenous ligands have been identified: oxysterols, including 25-hydroxycholesterol, act as agonists, enhancing transcription, whereas 7α-hydroxycholesterol serves as an inverse agonist, inhibiting function. This ligand-dependent regulation provides a mechanistic basis for pharmacological targeting.

Th17 Differentiation and Immune Homeostasis

RORγt is a key transcriptional regulator driving Th17 cell differentiation within the adaptive immune system. Naive CD4⁺ T cells exposed to TGF-β and IL-6 activate STAT3, inducing RORγt expression. RORγt directly binds conserved noncoding sequences (CNS2) within the IL17A, IL17F, and IL23R loci, promoting expression of Th17 signature cytokines. Additionally, RORγt forms a complex with RUNX1, remodeling chromatin accessibility to establish the Th17 differentiation program. Dysregulated RORγt activity contributes to pathological inflammation in autoimmune diseases such as rheumatoid arthritis, psoriasis, and multiple sclerosis. Preclinical studies using RORγt-specific inhibitors (e.g., A213, XY018) demonstrate significant attenuation of experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA), associated with reduced Th17 infiltration and inflammatory cytokine levels.

Primary Immunodeficiency Association

In 2015, the Casanova group at Rockefeller University reported a causal relationship between RORC mutations and primary immunodeficiency. The study began with a Pakistani child who developed fatal disseminated infection after BCG vaccination. Whole-genome sequencing identified a homozygous RORC mutation (c.395+1G>T). Additional mutations (e.g., R198X, T315M) were later found in families from Chile and Saudi Arabia. All patients exhibited chronic mucocutaneous candidiasis and susceptibility to mycobacterial infections. Mechanistically, RORC mutations cause triple immunodeficiency: defective IL-17 signaling due to impaired Th17 differentiation, reduced IFN-γ production in T cells upon mycobacterial antigen stimulation, and disrupted lymphoid tissue development via impaired lymphoid tissue inducer (LTi) function. These findings established RORC as a central regulator of antifungal and antimycobacterial immunity, providing a molecular diagnostic basis for immunodeficiency type 42 (IMD42).

Sepsis and Pulmonary Injury Regulation

In innate immunity, RORC contributes to the regulation of sepsis-induced inflammatory cascades. In a lipopolysaccharide (LPS)-induced sepsis model in rats, RORC expression in alveolar macrophages increased significantly 12 hours post-injection, coinciding with elevated serum IL-17 levels and aggravated acute lung injury. NF-κB activation drives RORC upregulation, and preventive administration of the NF-κB inhibitor PDTC reduces RORC expression, lung wet/dry weight ratio, and inflammatory cell infiltration. Pathologically, RORγt promotes IL-17-mediated neutrophil recruitment and tissue damage, while RORγ1 in hepatocytes regulates acute-phase proteins, amplifying systemic inflammation. This dual-level regulation positions RORC as a potential therapeutic target in sepsis.

Targeted Therapeutic Approaches and Challenges

Small-molecule inhibitors targeting RORC/LBD have advanced into preclinical development, including thiazolidinedione derivatives (e.g., SR2211), aryl sulfonamides (e.g., A213), and dihydroindole compounds (e.g., VTP. These compounds form hydrogen bonds with His479 and Tyr502 in the ligand-binding pocket, competitively inhibiting agonist binding and acting as inverse agonists. In CIA models, VTP-43742 reduces joint swelling and bone erosion without causing metabolic disturbances. Clinical translation faces challenges, including isoform selectivity (distinguishing RORγ1 from RORγt), tissue-specific targeting to limit off-target effects, and compensatory immunosuppression from long-term Th17 inhibition. Next-generation strategies include allosteric modulators targeting non-LBD domains, PROTAC-mediated spatiotemporal degradation of RORγt, and antisense oligonucleotides (ASOs) for tissue-specific mRNA regulation.

Conclusion and Outlook

RORC serves as a central transcriptional hub linking circadian rhythm, metabolic homeostasis, and immune balance. Future basic research should focus on isoform-specific functions in distinct tissue microenvironments, structural bases of ligand-RORC interactions, and post-translational modifications such as phosphorylation and acetylation. In translational medicine, individualized interventions are emerging: recombinant IFN-γ or IL-17 replacement for RORC-related immunodeficiency, localized delivery of RORγt inhibitors in autoimmune disease, and spatiotemporal modulation of RORC activity in sepsis to optimize clinical outcomes. As understanding of RORC biology deepens and intervention strategies refine, this transcriptional regulator holds promise for next-generation precision therapies in immune-related diseases.

Reference

Osorio-Rodríguez DA, Camacho BA, Ramírez-Segura C. Anti-ROR1 CAR-T cells: Architecture and performance. Front Med (Lausanne). 2023 Feb 17;10:1121020.
Michelini S, Ricci M, Serrani R, et al. Possible Role of the RORC Gene in Primary and Secondary Lymphedema: Review of the Literature and Genetic Study of Two Rare Causative Variants. Lymphat Res Biol. 2021 Apr;19(2):129-133.
Fauber BP, Magnuson S. Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc). J Med Chem. 2014 Jul 24;57(14):5871-92.
Sun SL, Xu HJ, Jiang XL, et al. Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis. J Med Chem. 2024 Nov 28;67(22):20315-20342.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry