Affinage

RORC

Nuclear receptor ROR-gamma · UniProt P51449

Round 2 corrected
Length
518 aa
Mass
58.2 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RORC encodes the nuclear receptor RORγ and its T-cell-specific isoform RORγt, serving as a master transcriptional regulator of type-17 immunity and lymphoid organ development. RORγt directly activates IL-17A transcription and silences PTGER2 in Th17 cells, and its ligand-binding domain is occupied by endogenous hydroxycholesterols and bile acid metabolites (e.g., 3-oxoLCA) that modulate coactivator recruitment to tune transcriptional output (PMID:20203100, PMID:31776512). In thymocytes, RORγ sustains Bcl-xL expression to prevent apoptosis and is essential for lymph node and Peyer's patch organogenesis, while in the periphery it defines ILC3 identity and drives IL-17 production by iNKT17, γδT17, and conventional Th17 cells (PMID:10875923, PMID:19029904, PMID:30602780). Bi-allelic loss-of-function RORC mutations in humans cause chronic mucocutaneous candidiasis and susceptibility to mycobacterial disease due to combined loss of IL-17- and IFN-γ-producing T cell subsets (PMID:26160376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 High

    Identification of RORγ as a novel orphan nuclear receptor established the existence of a third ROR subfamily member with tissue-selective expression, opening the question of its physiological function.

    Evidence cDNA cloning from human skeletal muscle with Northern blot expression profiling and chromosomal mapping

    PMID:7811290

    Open questions at the time
    • No ligand or target gene identified
    • Function in immune cells unknown
    • No loss-of-function data
  2. 2000 High

    Gene-targeted deletion revealed that RORγ is required for thymocyte survival via Bcl-xL regulation and for lymph node/Peyer's patch organogenesis, establishing its first in vivo functions.

    Evidence Two independent RORγ-knockout mouse lines with flow cytometry, TUNEL staining, and lymphoid organ histology

    PMID:10875923 PMID:10963675

    Open questions at the time
    • Mechanism of Bcl-xL transcriptional control not defined at the promoter level
    • Role of the T-cell-specific isoform (RORγt) not yet distinguished from full-length RORγ
  3. 2008 High

    RORγt was established as the lineage-defining transcription factor for Th17 differentiation, and Foxp3 was shown to directly bind and antagonize RORγt, explaining how TGF-β concentration reciprocally regulates Th17 versus Treg fate.

    Evidence Co-immunoprecipitation, domain-mapping mutagenesis, IL-17A promoter-luciferase assays, and in vitro Th17/Treg differentiation in mouse genetic models

    PMID:18368049 PMID:18434325

    Open questions at the time
    • Structural basis of Foxp3–RORγt interaction unknown
    • Endogenous ligand for RORγt LBD not yet identified
  4. 2008 High

    Discovery that RORγt marks an intestinal NKp46+ innate lymphoid subset (later classified as ILC3) producing IL-22 expanded RORγt's role beyond adaptive Th17 cells to innate immunity.

    Evidence RORγt-GFP reporter mice with flow cytometry and intracellular cytokine staining of intestinal lamina propria lymphocytes

    PMID:19029904

    Open questions at the time
    • Whether RORγt is continuously required for ILC3 maintenance versus initial specification was unresolved
  5. 2009 High

    Upstream regulation of RORC transcription was delineated: IL-27/STAT1 suppresses Rorc expression, while Notch/DLL4 signaling directly activates the Rorc promoter, placing RORγt as an integrator of cytokine and Notch inputs.

    Evidence STAT1-deficient T cells, Notch inhibition, Rorc promoter reporter assays, EAE and DTH in vivo models

    PMID:19380822 PMID:19494260

    Open questions at the time
    • Full cis-regulatory architecture of the RORC locus not mapped
    • Notch-Rorc promoter binding shown by reporter assay only, not ChIP
  6. 2010 High

    Crystal structures of the RORγ LBD bound to hydroxycholesterols identified the first endogenous ligands and showed that ligand occupancy stabilizes the active conformation for coactivator recruitment, resolving the receptor's 'orphan' status.

    Evidence X-ray crystallography of RORγ LBD, site-directed mutagenesis, coactivator peptide recruitment assays

    PMID:20203100

    Open questions at the time
    • Physiological relevance of hydroxycholesterol ligands in T cell differentiation not demonstrated in vivo
    • Selectivity among different oxysterol species unclear
  7. 2014 High

    ChIP-seq in Th17 cells revealed RORγt directly binds and silences PTGER2, uncovering a repressive function beyond its well-known activating role on IL-17, with clinical relevance in multiple sclerosis patients.

    Evidence ChIP-seq in mouse Th17 cells, RORC siRNA knockdown in human Th17 cells, EP2 gain-of-function, MS patient immunophenotyping

    PMID:24812667

    Open questions at the time
    • Genome-wide repressive target repertoire of RORγt not fully catalogued
    • Mechanism of transcriptional repression (corepressor identity) not defined
  8. 2015 High

    Human bi-allelic RORC loss-of-function mutations demonstrated that both RORγ isoforms are essential for mucocutaneous and systemic immunity, causing candidiasis and mycobacterial susceptibility through combined loss of IL-17 and impaired IFN-γ production by γδ T cells.

    Evidence Identification of patients with homozygous RORC mutations, deep immunophenotyping, cytokine production assays across multiple kindreds

    PMID:26160376

    Open questions at the time
    • How RORγ regulates IFN-γ production mechanistically remains undefined
    • Whether full-length RORγ versus RORγt is responsible for the mycobacterial phenotype is unresolved
  9. 2016 High

    Pharmacological and temporal genetic ablation showed that ongoing RORγt activity is required to maintain Th17 cytokine output but is dispensable for ILC3 effector function, resolving a key question about differential RORγt dependency across lymphocyte lineages.

    Evidence Pharmacological RORγt inhibition in mice, conditional/temporal Rorc deletion, infection models, IBD patient tissue analysis

    PMID:26878233

    Open questions at the time
    • Molecular basis for differential RORγt dependency in ILC3 versus Th17 cells unknown
    • Long-term consequences of RORγt inhibition on ILC3 homeostasis not assessed
  10. 2019 High

    The bile acid metabolite 3-oxoLCA was identified as a direct endogenous RORγt antagonist linking gut microbial metabolism to Th17/Treg balance, and NFAT/NF-κB-dependent cis-regulatory elements at the RORC locus were mapped, completing a circuit from TCR signaling to RORγt expression.

    Evidence Bile acid library screen with direct LBD binding assays and intestinal Th17 analysis; CRISPR/Cas9 deletion of RORC cis-elements with ChIP and histone modification profiling in human CD4+ T cells

    PMID:31619674 PMID:31776512

    Open questions at the time
    • In vivo contribution of 3-oxoLCA to intestinal RORγt regulation quantitatively uncertain
    • Interplay between NFAT/NF-κB elements and Notch-responsive elements at the RORC locus not integrated
  11. 2022 High

    RORα was found to cooperatively bind with RORγt to a Rorc cis-regulatory element required for sustained RORγt expression and Th17 lineage stability in vivo, revealing a feed-forward loop between the two ROR family members.

    Evidence T-cell-specific RORα conditional knockout, ChIP assays, CRISPR/Cas9 deletion of the cooperative binding element, in vivo Th17 analysis

    PMID:36243007

    Open questions at the time
    • Structural basis of cooperative RORα/RORγt DNA binding unknown
    • Whether this feed-forward loop operates in ILC3 or other RORγt+ lineages not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the genome-wide repressive target repertoire of RORγt, the structural basis of the Foxp3–RORγt interaction, the mechanism by which RORγ controls IFN-γ production, and how microbiota-derived ligands quantitatively tune RORγt activity across different tissue niches in vivo.
  • No structural model of Foxp3–RORγt complex
  • Mechanism of RORγ-dependent IFN-γ regulation unknown
  • Quantitative in vivo contributions of individual endogenous ligands not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4 GO:0008289 lipid binding 3
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 2 R-HSA-5357801 Programmed Cell Death 2
Partners
BCL2L1FOXP3IL17APTGER2RORA

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RORγ (encoded by RORC) was identified as a novel member of the nuclear receptor superfamily, belonging to the ROR/RZR orphan receptor subfamily. It encodes a 560-amino-acid protein (~63 kDa) with a DNA-binding domain highly homologous to RORα/RZRα and RZRβ, and is most highly expressed in skeletal muscle, with the gene localized to human chromosome 1. cDNA cloning, Northern blot analysis, chromosomal localization Biochemical and biophysical research communications High 7811290
2000 RORγ is required for thymocyte survival: mice lacking RORγ show loss of thymic Bcl-xL expression, increased apoptosis of CD4+CD8+ thymocytes, and failure of positive selection. RORγ is also essential for lymph node and Peyer's patch organogenesis, associated with loss of a CD3-CD4+CD45+ lymphoid tissue-inducer progenitor population. Targeted gene disruption (knockout mice), flow cytometry, TUNEL staining, Bcl-xL expression analysis Science High 10875923 10963675
2000 RORγ knockout mice exhibit a 4-fold increase in thymocyte apoptosis associated with greatly reduced Bcl-XL expression, and a 6-fold rise in S-phase cells among thymocytes, establishing RORγ as a negative regulator of apoptosis in thymocytes, likely through transcriptional control of Bcl-XL. Targeted disruption of RORγ, TUNEL staining, annexin V staining, flow cytometry, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 10963675
2008 RORγt (the T-cell-specific isoform encoded by RORC) drives Th17 cell differentiation and IL-17A transcription. Foxp3, induced by high concentrations of TGF-β, directly binds RORγt protein and inhibits its transcriptional activity, thereby suppressing IL-17 production and Th17 differentiation. IL-6 and IL-21 relieve Foxp3-mediated inhibition of RORγt to promote Th17 differentiation. Genetic mouse models, co-immunoprecipitation, reporter assays, cytokine measurement, in vitro differentiation assays Nature High 18368049
2008 Foxp3 directly interacts with RORγt through the exon 2 region of Foxp3 and inhibits RORγt-mediated IL-17A promoter activation. The exon 2 region and forkhead (FKH) domain of Foxp3 are both necessary for suppression of RORγt transcriptional activity on the IL-17A minimum promoter. Reporter gene assays (IL-17A promoter-luciferase), co-immunoprecipitation, domain mapping by deletion mutagenesis The Journal of biological chemistry High 18434325
2008 RORγt expression defines a previously unrecognized NKp46+CD3- lymphocyte subset in the intestinal lamina propria that produces IL-22 but has diminished degranulation and IFN-γ capacity. RORγt, previously known for its role in lymphoid tissue-inducer cell development, is thus required for this innate lymphoid subset's identity and function. Flow cytometry, intracellular cytokine staining, RORγt-GFP reporter mice, functional cytotoxicity and cytokine assays Nature immunology High 19029904
2009 IL-27 suppresses Th17 development by inhibiting RORγt (RORc) expression in a STAT1-dependent manner. IL-27 acts upstream of RORγt transcription to block IL-17A and IL-17F production during TGF-β plus IL-6 or IL-23-driven Th17 differentiation in both mouse and human systems. Cytokine treatment, gene expression analysis, STAT1-deficient cells, in vivo EAE and DTH models with IL-27p28-deficient mice Journal of immunology High 19380822
2009 Notch ligand DLL4, induced on dendritic cells by TLR activation, upregulates Rorc expression in T cells and directly promotes IL-17 production. Both the Rorc and Il17 gene promoters are direct transcriptional Notch targets, establishing a DLL4-Notch-RORγt-IL-17 axis in Th17 differentiation. In vitro T cell culture with DLL4, gene expression analysis, promoter reporter assays for Rorc and Il17, Notch inhibitor experiments Journal of immunology Medium 19494260
2010 Hydroxycholesterols function as natural ligands of RORγ by binding in the ligand-binding domain (LBD) and promoting coactivator recruitment. Crystal structures of the RORγ LBD bound to multiple hydroxycholesterols reveal binding modes in the canonical active conformation; mutations disrupting hydroxycholesterol binding abolish constitutive RORγ activity. Crystal structure determination of RORγ LBD, biochemical coactivator recruitment assays, site-directed mutagenesis Molecular endocrinology High 20203100
2011 Ursolic acid (UA), a natural small molecule, selectively inhibits RORγt transcriptional function, resulting in decreased IL-17 expression in developing and differentiated Th17 cells and amelioration of EAE in vivo. UA acts as a selective RORγt antagonist without broadly affecting other nuclear receptors. In vitro Th17 differentiation, reporter gene assays, IL-17 ELISA, EAE mouse model, selectivity profiling The Journal of biological chemistry Medium 21566134
2014 RORC (RORγt) directly silences PTGER2 (encoding prostaglandin receptor EP2) transcription in Th17 cells. Chromatin immunoprecipitation-sequencing (ChIP-seq) in mouse Th17 cells showed RORγt binds directly to the Ptger2 locus; RORC knockdown in human Th17 cells restored EP2 expression. In MS patients, reduced RORC binding to the PTGER2 promoter correlated with higher EP2 levels and a pathogenic Th17 phenotype (elevated IFN-γ and GM-CSF). ChIP-seq, RORC knockdown (siRNA), gene expression analysis, EP2 overexpression in primary human Th17 cells The Journal of clinical investigation High 24812667
2014 RORγ (RORc) and RORα expressed in human skin serve as receptors for endogenously produced noncalcemic vitamin D derivatives (20(OH)D3 and 20,23(OH)2D3), which act as antagonists/inverse agonists. This was demonstrated by ligand binding assays, ROR-responsive element luciferase reporter assays, and molecular docking to crystal structures of RORα and RORγ LBDs, with 20(OH)D3 inhibiting IL-17 promoter activity in cells overexpressing RORγ. Stable cell line reporter assays, mammalian 2-hybrid LBD interaction assay, molecular docking, IL-17 promoter-luciferase assay FASEB journal Medium 24668754
2014 RORc (RORγ) structural biology and pharmacology: the LBD of RORc adopts an active conformation and is amenable to small-molecule modulation. Inverse agonists occupying the ligand-binding pocket suppress coactivator recruitment and IL-17 production, providing a structural basis for targeting RORc in autoimmune disease. Review integrating crystal structures, biochemical assays, medicinal chemistry SAR, cellular IL-17 inhibition assays Journal of medicinal chemistry Medium 24502334
2015 Bi-allelic loss-of-function mutations in RORC in humans result in absence of IL-17A/F-producing T cells (explaining chronic mucocutaneous candidiasis) and unexpectedly impaired IFN-γ production, particularly by circulating γδ T cells and CD4+CCR6+CXCR3+ αβ T cells, demonstrating that both RORγ and RORγT isoforms are required for systemic immunity to Mycobacterium in humans. Human genetics (bi-allelic RORC mutations), immunophenotyping of patient cells, cytokine production assays, T cell subset analysis Science High 26160376
2015 Potent and selective imidazo[1,5-a]pyridine and -pyrimidine compounds were identified as RORc inverse agonists with >300-fold selectivity over other ROR family members and other nuclear receptors, demonstrating that inverse agonist occupancy of the RORc LBD suppresses IL-17 production in human primary cells. Biochemical binding assays, cellular selectivity profiling, IL-17 suppression in human primary cells Bioorganic & medicinal chemistry letters Medium 26048793
2016 Transient pharmacological inhibition of ROR-γt (encoded by Rorc) selectively reduces cytokine production from TH17 cells but not from group 3 ILCs (ILC3s) in vivo. Temporal deletion of Rorc in mature ILCs did not impair their cytokine response, revealing that ongoing ROR-γt activity is differentially required for TH17 maintenance versus ILC3 function. Pharmacological ROR-γt inhibition in mice, conditional/temporal Rorc deletion, infection models, cytokine assays, IBD patient tissue analysis Nature medicine High 26878233
2019 The bile acid metabolite 3-oxoLCA inhibits TH17 cell differentiation by directly binding to RORγt (encoded by RORC) and blocking coactivator recruitment. Biochemical binding assays confirmed direct physical interaction between 3-oxoLCA and the RORγt LBD, establishing bile acid metabolites as endogenous RORγt ligands that modulate the TH17/Treg balance in the intestine. Bile acid metabolite library screen, direct binding assays (competitive binding to RORγt LBD), Th17 differentiation assays, in vivo intestinal lamina propria analysis Nature High 31776512
2019 NFAT proteins bind to newly defined regulatory elements at the human RORC locus and activate RORγt transcription in cooperation with NF-κB in CD4+ T cells. T cell receptor stimulation induces cyclosporine A-sensitive (calcineurin/NFAT-dependent) histone modifications and P300/CBP acetylase recruitment at these RORC regulatory elements; CRISPR/Cas9-guided deletion of these elements reduced RORγt expression. CRISPR/Cas9 deletion of regulatory elements, ChIP assays, NFAT overexpression/inhibition (cyclosporine A), histone modification analysis, reporter assays Nature communications High 31619674
2019 RORγt+ iNKT and γδ-T cell subsets expressing a Th17-like profile are enriched in inflamed joints of spondyloarthritis patients and act as major IL-17 secretors. RORγt inhibition blocks IL-17 production by these innate-like T cells while selectively sparing IL-22-producing subsets, demonstrating that RORγt is required for the IL-17 effector program of both iNKT17 and γδ17 cells. Flow cytometry, gene expression profiling, RORγt pharmacological inhibition, cytokine production assays in patient cells and healthy donors Nature communications Medium 30602780
2022 RORα cooperatively binds with RORγt to a previously unidentified Rorc cis-regulatory element and is required for maintenance of RORγt expression and Th17 effector function in peripheral tissues in vivo. RORα-deficient T cells show reduced RORγt expression and impaired Th17 responses, while cooperative RORα/RORγt binding to this element is essential for Th17 lineage stability. T cell-specific RORα conditional knockout mice, ChIP assays, CRISPR/Cas9 deletion of Rorc cis-regulatory element, flow cytometry, cytokine assays, in vivo tissue analysis Immunity High 36243007

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 TOR signaling in growth and metabolism. Cell 4640 16469695
2012 Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 3725 23128233
2000 TOR, a central controller of cell growth. Cell 1628 11057898
2008 TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 1563 18368049
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2019 Bile acid metabolites control TH17 and Treg cell differentiation. Nature 1091 31776512
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 Tor-mediated induction of autophagy via an Apg1 protein kinase complex. The Journal of cell biology 942 10995454
2017 Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 934 28473536
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 690 22174183
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2013 Glucose-TOR signalling reprograms the transcriptome and activates meristems. Nature 614 23542588
2000 Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science (New York, N.Y.) 603 10875923
2020 AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. Cell metabolism 602 32130880
2017 Nutrient sensing and TOR signaling in yeast and mammals. The EMBO journal 572 28096180
2010 With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell metabolism 504 20519118
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2014 The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 489 24828042
2001 The target of rapamycin (TOR) proteins. Proceedings of the National Academy of Sciences of the United States of America 485 11416184
2003 Tor signalling in bugs, brain and brawn. Nature reviews. Molecular cell biology 478 12563289
2008 Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nature immunology 477 19029904
2011 Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 467 22170608
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1997 TOR signalling and control of cell growth. Current opinion in cell biology 415 9425342
2005 The expanding TOR signaling network. Current opinion in cell biology 403 15780592
2003 Rheb fills a GAP between TSC and TOR. Trends in biochemical sciences 392 14607085
2008 Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. The Journal of biological chemistry 353 18434325
2015 IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science (New York, N.Y.) 336 26160376
2008 Aging: ROS or TOR. Cell cycle (Georgetown, Tex.) 310 18971624
2016 TOR Signaling and Nutrient Sensing. Annual review of plant biology 309 26905651
2008 The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 302 18670193
2008 Amino acid regulation of TOR complex 1. American journal of physiology. Endocrinology and metabolism 294 18765678
2010 Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. Journal of reproductive immunology 288 20106535
2002 Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae. Microbiology and molecular biology reviews : MMBR 285 12456783
2001 The TOR kinases link nutrient sensing to cell growth. The Journal of biological chemistry 284 11266435
2009 IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. Journal of immunology (Baltimore, Md. : 1950) 273 19380822
1998 The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. The EMBO journal 270 9843498
2005 The TOR and EGO protein complexes orchestrate microautophagy in yeast. Molecular cell 267 15989961
2000 Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proceedings of the National Academy of Sciences of the United States of America 266 10963675
2009 The TOR pathway comes of age. Biochimica et biophysica acta 263 19539012
2009 Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proceedings of the National Academy of Sciences of the United States of America 251 19439651
2003 TOR signaling. Science's STKE : signal transduction knowledge environment 249 14668532
2003 Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes & development 241 12654728
2014 RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 237 24668754
1999 Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Current opinion in genetics & development 236 10072357
2008 Insulin/TOR signaling in growth and homeostasis: a view from the fly world. The international journal of biochemistry & cell biology 233 18992839
2016 Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nature medicine 223 26878233
2011 Rapamycin and glucose-target of rapamycin (TOR) protein signaling in plants. The Journal of biological chemistry 219 22134914
2009 TOR complex 2: a signaling pathway of its own. Trends in biochemical sciences 214 19875293
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1994 ROR gamma: the third member of ROR/RZR orphan receptor subfamily that is highly expressed in skeletal muscle. Biochemical and biophysical research communications 205 7811290
2002 Nuclear hormone receptors in T lymphocytes. Cell 204 11983153
2019 RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients. Nature communications 198 30602780
2011 Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORgamma t protein. The Journal of biological chemistry 191 21566134
2010 Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Molecular endocrinology (Baltimore, Md.) 187 20203100
2011 Amino acid signaling in TOR activation. Annual review of biochemistry 181 21548787
2012 Sensing nutrient and energy status by SnRK1 and TOR kinases. Current opinion in plant biology 163 22305521
2006 The amino acid sensitive TOR pathway from yeast to mammals. FEBS letters 162 16684541
2008 TOR regulation of AGC kinases in yeast and mammals. The Biochemical journal 159 18215152
2012 Organ size control by Hippo and TOR pathways. Current biology : CB 156 22575479
2018 TOR signaling in plants: conservation and innovation. Development (Cambridge, England) 155 29986898
2009 Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. Journal of immunology (Baltimore, Md. : 1950) 154 19494260
2014 Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc). Journal of medicinal chemistry 149 24502334
2004 Autophagy in yeast: a TOR-mediated response to nutrient starvation. Current topics in microbiology and immunology 146 14560952
2016 Shaping plant development through the SnRK1-TOR metabolic regulators. Current opinion in plant biology 138 28027512
2006 Complexity of the TOR signaling network. Trends in cell biology 138 16516475
2014 The TOR signaling pathway regulates vegetative development and virulence in Fusarium graminearum. The New phytologist 125 24684168
2012 The evolution of the TOR pathway and its role in cancer. Oncogene 123 23246968
2019 Integration of nutrient, energy, light, and hormone signalling via TOR in plants. Journal of experimental botany 115 30715492
2021 Diverse nitrogen signals activate convergent ROP2-TOR signaling in Arabidopsis. Developmental cell 114 33831352
2019 TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging. Genetics 110 31594908
2015 Novel links in the plant TOR kinase signaling network. Current opinion in plant biology 108 26476687
2011 Evolution of the TOR pathway. Journal of molecular evolution 108 22057117
2006 Thinking globally and acting locally with TOR. Current opinion in cell biology 108 17046229
2011 A longer and healthier life with TOR down-regulation: genetics and drugs. Biochemical Society transactions 103 21428920
2006 Regulation of chemotaxis by the orchestrated activation of Ras, PI3K, and TOR. European journal of cell biology 103 16740339
2017 Evolutionary Conservation of the Components in the TOR Signaling Pathways. Biomolecules 97 29104218
2004 Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila. Cell 96 15454083
2008 Nutritional control via Tor signaling in Saccharomyces cerevisiae. Current opinion in microbiology 95 18396450
2017 EGFR-dependent TOR-independent endocycles support Drosophila gut epithelial regeneration. Nature communications 93 28485389
2010 TOR signaling never gets old: aging, longevity and TORC1 activity. Ageing research reviews 92 20385253
1996 Identification and characterization of an endogenous ligand for opioid receptor homologue ROR-C: its involvement in allodynic response to innocuous stimulus. Brain research. Molecular brain research 91 9037523
2020 TOR dynamically regulates plant cell-cell transport. Proceedings of the National Academy of Sciences of the United States of America 90 32051250
2006 Mitochondrial signaling, TOR, and life span. Biological chemistry 88 17081107
2012 Regulation of TOR by small GTPases. EMBO reports 87 22240970
2011 TOR and ageing: a complex pathway for a complex process. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 85 21115526
2022 Glucose-driven TOR-FIE-PRC2 signalling controls plant development. Nature 83 36104568
2010 The TOR pathway modulates the structure of cell walls in Arabidopsis. The Plant cell 83 20530756
2001 TOR modulates GCN4-dependent expression of genes turned on by nitrogen limitation. Journal of bacteriology 80 11244074
2007 TOR signaling is a determinant of cell survival in response to DNA damage. Molecular and cellular biology 76 17698581
2022 Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity 73 36243007
2017 TOR, the Gateway to Cellular Metabolism, Cell Growth, and Disease. Cell 70 28888322
2015 Regulation of ribosomal DNA amplification by the TOR pathway. Proceedings of the National Academy of Sciences of the United States of America 67 26195783
2007 Structure of TOR and its complex with KOG1. Molecular cell 66 17679098
2022 ABA represses TOR and root meristem activity through nuclear exit of the SnRK1 kinase. Proceedings of the National Academy of Sciences of the United States of America 60 35787039
2011 Activating mutations of TOR (target of rapamycin). Genes to cells : devoted to molecular & cellular mechanisms 60 21210909
2020 A Tour of TOR Complex Signaling in Plants. Trends in biochemical sciences 59 33309324
2014 Balancing act: matching growth with environment by the TOR signalling pathway. Journal of experimental botany 59 24567496
2011 Regulation of plant growth and metabolism by the TOR kinase. Biochemical Society transactions 59 21428923
2021 Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition. Nature cell biology 58 33495632
2019 Mutations of the AtYAK1 Kinase Suppress TOR Deficiency in Arabidopsis. Cell reports 56 31216485
2015 Activation of the TOR Signalling Pathway by Glutamine Regulates Insect Fecundity. Scientific reports 55 26024507
2004 The role of phosphatases in TOR signaling in yeast. Current topics in microbiology and immunology 51 14560949
2004 TOR action in mammalian cells and in Caenorhabditis elegans. Current topics in microbiology and immunology 50 14560955
2013 Evolutionarily conserved regulation of TOR signalling. Journal of biochemistry 49 23698095
2021 Light regulates alternative splicing outcomes via the TOR kinase pathway. Cell reports 48 34496244
2020 The Importance of TOR Kinase in Plant Development. Frontiers in plant science 48 32117365
2015 Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. Bioorganic & medicinal chemistry letters 46 26048793
2022 The RALF1-FERONIA complex interacts with and activates TOR signaling in response to low nutrients. Molecular plant 45 35585790
2018 The Arabidopsis THADA homologue modulates TOR activity and cold acclimation. Plant biology (Stuttgart, Germany) 43 30098100
2016 Target of Rapamycin (TOR) Regulates Growth in Response to Nutritional Signals. Microbiology spectrum 41 27763256
2010 P66SHC and ageing: ROS and TOR? Aging 40 20689155
2016 Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis. International archives of allergy and immunology 39 27902985
2021 TOR Signaling Pathway in Cardiac Aging and Heart Failure. Biomolecules 37 33513917
2010 Evolution of the TSC1/TSC2-TOR signaling pathway. Science signaling 36 20587805
2014 Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. The Journal of clinical investigation 35 24812667
2007 TOR-in(g) the nucleus. Cell cycle (Georgetown, Tex.) 34 17245124
2020 The flipside of the TOR coin - TORC2 and plasma membrane homeostasis at a glance. Journal of cell science 33 32393676
2020 Structural Insights into TOR Signaling. Genes 33 32759652
2019 NFAT primes the human RORC locus for RORγt expression in CD4+ T cells. Nature communications 33 31619674
2008 What controls TOR? IUBMB life 33 18493947
2007 TOR signaling and S6 kinase 1: Yeast catches up. Cell metabolism 33 17618850
2022 Photosynthetic assimilation of CO2 regulates TOR activity. Proceedings of the National Academy of Sciences of the United States of America 32 34996872
2022 α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease. Brain, behavior, and immunity 32 36343753
2019 ROS Inhibits Cell Growth by Regulating 4EBP and S6K, Independent of TOR, during Development. Developmental cell 32 31063760