Affinage

RTRAF

tRNA-splicing ligase complex subunit RTRAF · UniProt Q9Y224

Length
244 aa
Mass
28.1 kDa
Annotated
2026-06-10
100 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RTRAF (hCLE/CGI-99/C14orf166) is a multifunctional positive modulator of gene expression that acts at both the transcriptional and translational levels (PMID:16950395, PMID:30833903). In the nucleus it co-immunoprecipitates with multiple phosphorylated forms of the RNA polymerase II largest subunit, localizes to sites of active mRNA synthesis, and is required for normal Pol II transcript output, with its silencing causing broad downregulation of gene expression (PMID:16950395). In the cytoplasm it assembles a cap-binding complex with DDX1, HSPC117, and FAM98B that associates with the mRNA cap independently of eIF4E and promotes translation, with the partner proteins stabilizing each other and enhancing RTRAF's intrinsically low cap affinity (PMID:30833903). RTRAF also engages the influenza A virus polymerase complex and is required for viral RNA transcription, replication, and particle production, indicating that its gene-expression machinery is co-opted during infection (PMID:21900157). Through its C-terminal domain it homodimerizes and binds the centrosomal protein ninein, blocking ninein phosphorylation by GSK3beta, while its N-terminal region carries transcriptional activity (PMID:15147888). In breast cancer cells RTRAF drives autocrine IL-6/STAT3 signaling by increasing Pol II and p300 occupancy at the IL-6 promoter, promoting cancer stem cell properties and metastasis (PMID:28166202).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2004 Medium

    Established the first physical partner and domain architecture of RTRAF, defining a C-terminal homodimerization/ninein-binding region and an N-terminal region with transcriptional activity, and showing RTRAF can shield a substrate from GSK3beta phosphorylation.

    Evidence Yeast two-hybrid screen, GST pull-down, in vitro kinase assay, and transcriptional activity assay

    PMID:15147888

    Open questions at the time
    • Functional consequence of blocking ninein phosphorylation in cells not established
    • No structural model of the homodimer or ninein interface
    • Link between centrosomal role and transcriptional/translational roles unresolved
  2. 2006 Medium

    Defined RTRAF as a positive modulator of RNA polymerase II transcription, answering whether its nuclear localization reflects a functional role in mRNA synthesis.

    Evidence Co-IP with Pol II, confocal colocalization, Br-UTP incorporation, RNAi knockdown with microarray profiling

    PMID:16950395

    Open questions at the time
    • Direct mechanism by which RTRAF enhances Pol II activity not defined
    • Whether RTRAF binds Pol II directly or through other factors unknown
    • No genome-wide occupancy data for RTRAF itself
  3. 2011 Medium

    Showed RTRAF is a host factor co-opted by influenza virus, linking its gene-expression function to support of viral polymerase activity.

    Evidence Co-IP with viral polymerase complex, confocal colocalization with viral RNPs, siRNA knockdown with viral activity, titer, and replication readouts

    PMID:21900157

    Open questions at the time
    • Whether RTRAF acts on viral transcription via its cellular Pol II/translation roles or independently unclear
    • Direct binding contact with viral polymerase subunits not mapped
  4. 2012 Low

    Identified PTPIP51 as a RTRAF partner with a mitotic equatorial-plate localization, extending the protein's interactome to mitotic/cytoskeletal contexts.

    Evidence In vitro binding, in vivo co-IP, Duolink proximity ligation assay, confocal microscopy

    PMID:24970130

    Open questions at the time
    • Single lab with limited mechanistic follow-up beyond complex localization
    • Functional consequence of the PTPIP51 interaction not established
    • No connection drawn to RTRAF's transcription or translation functions
  5. 2017 Medium

    Connected RTRAF's transcriptional modulator activity to a disease-relevant program by showing it drives autocrine IL-6/STAT3 signaling and metastasis in breast cancer.

    Evidence ChIP for Pol II and p300 at the IL-6 promoter, STAT3 activity assay, siRNA knockdown, in vivo colonization, and tocilizumab rescue

    PMID:28166202

    Open questions at the time
    • Whether RTRAF acts directly at the IL-6 promoter or via Pol II/p300 recruitment indirectly not resolved
    • Selectivity for IL-6 versus genome-wide promoters not addressed
  6. 2019 High

    Defined RTRAF's cytoplasmic role by establishing it as a subunit of an eIF4E-independent cap-binding complex that promotes translation, answering how RTRAF contributes to gene expression beyond transcription.

    Evidence Co-IP, cap-analog resin pulldown with competition/elution, purified-protein cap-binding, siRNA knockdown with translation assay, RIP-seq

    PMID:30833903

    Open questions at the time
    • Stoichiometry and structure of the DDX1/HSPC117/FAM98B/RTRAF complex not solved
    • How nuclear transcription and cytoplasmic translation roles are coordinated unknown
    • Mechanism by which partners boost RTRAF cap affinity not defined at atomic level

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RTRAF's distinct nuclear (Pol II transcription), cytoplasmic (cap-binding translation), centrosomal (ninein/GSK3beta), and mitotic (PTPIP51) activities are integrated into a single coherent cellular function remains unresolved.
  • No unifying structural or regulatory model links the transcription, translation, and centrosomal functions
  • Spatiotemporal partitioning of RTRAF among its complexes not characterized
  • No structure of any RTRAF complex available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1 GO:0045182 translation regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 2 R-HSA-392499 Metabolism of proteins 1 R-HSA-8953854 Metabolism of RNA 1
Partners
DDX1FAM98BHSPC117NINEINPOLR2APTPIP51
Complex memberships
hCLE/DDX1/HSPC117/FAM98B cap-binding complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 hCLE/CGI-99 (RTRAF) co-immunoprecipitates with different phosphorylated forms of RNA polymerase II (RNAP II) largest subunit and colocalizes with RNAP II by confocal microscopy. hCLE localizes to nuclear sites of active mRNA synthesis (colocalization with Br-UTP incorporation sites). RNAi-mediated silencing of hCLE reduced RNAP II transcript synthesis by ~50%, and microarray analysis showed >90% of differentially expressed genes were downregulated, establishing hCLE as a positive modulator of RNAP II transcriptional activity. Co-immunoprecipitation, confocal microscopy colocalization, in situ Br-UTP incorporation, RNAi knockdown, microarray expression profiling Journal of molecular biology Medium 16950395
2004 CGI-99 (RTRAF) physically interacts with the C-terminal domain of human ninein (hNinein), as demonstrated by yeast two-hybrid screening and in vitro GST pull-down assay. CGI-99 forms homodimers via its C-terminal domain (which overlaps with the hNinein binding site). In a kinase assay, CGI-99 binding to hNinein completely blocks phosphorylation of hNinein by GSK3beta. The N-terminal region of CGI-99 harbors transcriptional activity. Yeast two-hybrid screening, GST pull-down assay, in vitro kinase assay, transcriptional activity assay FEBS letters Medium 15147888
2011 hCLE/C14orf166 (RTRAF) interacts with the influenza A virus polymerase complex (not just PA subunit alone) and colocalizes with viral ribonucleoproteins in infected cells. Silencing of hCLE reduces viral polymerase activity, viral RNA transcription, viral RNA replication, virus titer, and viral particle production, establishing hCLE as a host cellular factor required for influenza virus replication. Co-immunoprecipitation, confocal microscopy colocalization, siRNA knockdown with viral polymerase activity assay, viral titer measurement Journal of virology Medium 21900157
2012 PTPIP51 (regulator of microtubule dynamics protein 3) interacts with CGI-99 (RTRAF) both in vitro and in vivo. The PTPIP51/CGI-99 complex localizes to the equatorial region during mitosis. Duolink proximity ligation assays confirmed in-cell association of PTPIP51 with CGI-99. In vitro binding assay, in vivo co-immunoprecipitation, Duolink proximity ligation assay, confocal microscopy Biomolecules Low 24970130
2017 CGI-99 (RTRAF) activates autocrine IL-6/STAT3 signaling in breast cancer cells by increasing accumulation and activity of RNA polymerase II and the p300 cofactor at the proximal promoter of IL-6. This mechanism drives breast cancer stem cell properties and lung colonization in vivo. The IL-6 receptor antibody tocilizumab abrogates CGI-99-induced metastasis in vivo, placing CGI-99 upstream of the IL-6/STAT3 axis. ChIP (RNA Pol II and p300 at IL-6 promoter), in vivo tumor colonization assay, STAT3 activity assay, siRNA knockdown, tocilizumab rescue experiment Oncogene Medium 28166202
2019 hCLE/RTRAF forms a cap-binding complex with DDX1, HSPC117, and FAM98B in HEK293T cells. All four proteins bind to cap analog-containing resins. Competition and elution experiments show that hCLE complex binding to cap resins is independent of eIF4E. Purified hCLE alone binds cap with low affinity, indicating that interacting proteins modulate its cap association. hCLE silencing reduces accumulation of complex partners and decreases mRNA translation. RNAs associated with hCLE are enriched for mRNAs involved in translation. Co-immunoprecipitation, cap analog resin pulldown, competition/elution binding assay, purified protein cap-binding assay, siRNA knockdown with translation assay, RNA immunoprecipitation and sequencing Frontiers in physiology High 30833903

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Dodeca-CLE peptides as suppressors of plant stem cell differentiation. Science (New York, N.Y.) 491 16902140
2008 Non-cell-autonomous control of vascular stem cell fate by a CLE peptide/receptor system. Proceedings of the National Academy of Sciences of the United States of America 410 18812507
2021 Enhancing grain-yield-related traits by CRISPR-Cas9 promoter editing of maize CLE genes. Nature plants 282 33619356
2008 Nod factor/nitrate-induced CLE genes that drive HAR1-mediated systemic regulation of nodulation. Plant & cell physiology 280 19074184
2013 Root-derived CLE glycopeptides control nodulation by direct binding to HAR1 receptor kinase. Nature communications 260 23934307
2014 CLE-CLAVATA1 peptide-receptor signaling module regulates the expansion of plant root systems in a nitrogen-dependent manner. Proceedings of the National Academy of Sciences of the United States of America 242 24449877
2010 CLE peptides control Medicago truncatula nodulation locally and systemically. Plant physiology 241 20348212
2011 Inoculation- and nitrate-induced CLE peptides of soybean control NARK-dependent nodule formation. Molecular plant-microbe interactions : MPMI 208 21198362
2008 Plant CLE peptides from two distinct functional classes synergistically induce division of vascular cells. Proceedings of the National Academy of Sciences of the United States of America 173 19011104
2006 Evidence for functional conservation, sufficiency, and proteolytic processing of the CLAVATA3 CLE domain. Plant physiology 138 16407446
2013 WUSCHEL-RELATED HOMEOBOX4 is involved in meristem maintenance and is negatively regulated by the CLE gene FCP1 in rice. The Plant cell 120 23371950
2016 CLE peptides and their signaling pathways in plant development. Journal of experimental botany 119 27229733
2016 Crystal structure of PXY-TDIF complex reveals a conserved recognition mechanism among CLE peptide-receptor pairs. Cell research 111 27055373
2012 Transcriptional and functional classification of the GOLVEN/ROOT GROWTH FACTOR/CLE-like signaling peptides reveals their role in lateral root and hair formation. Plant physiology 111 23370719
2012 Nodule numbers are governed by interaction between CLE peptides and cytokinin signaling. The Plant journal : for cell and molecular biology 98 22168914
2010 CLE peptides can negatively regulate protoxylem vessel formation via cytokinin signaling. Plant & cell physiology 98 20802224
2008 Functional diversification of CLAVATA3-related CLE proteins in meristem maintenance in rice. The Plant cell 96 18676878
2020 The NIN transcription factor coordinates CEP and CLE signaling peptides that regulate nodulation antagonistically. Nature communications 95 32576831
2010 Dual roles for the variable domain in protein trafficking and host-specific recognition of Heterodera glycines CLE effector proteins. The New phytologist 91 20497349
2011 Soybean nodule-enhanced CLE peptides in roots act as signals in GmNARK-mediated nodulation suppression. Plant & cell physiology 84 21757457
2018 The CLAVATA receptor FASCIATED EAR2 responds to distinct CLE peptides by signaling through two downstream effectors. eLife 83 29543153
2017 Perception of root-active CLE peptides requires CORYNE function in the phloem vasculature. EMBO reports 83 28607033
2008 The CLE family of plant polypeptide signaling molecules. Cellular and molecular life sciences : CMLS 79 18034320
2009 Structural and functional diversity of CLAVATA3/ESR (CLE)-like genes from the potato cyst nematode Globodera rostochiensis. Molecular plant-microbe interactions : MPMI 78 19656047
2011 The Function of the CLE Peptides in Plant Development and Plant-Microbe Interactions. The arabidopsis book 75 22303273
2019 A CLE-SUNN module regulates strigolactone content and fungal colonization in arbuscular mycorrhiza. Nature plants 74 31477892
2010 Characterization of a CLE processing activity. Plant molecular biology 71 21052783
2017 Identification of cyst nematode B-type CLE peptides and modulation of the vascular stem cell pathway for feeding cell formation. PLoS pathogens 67 28158306
2011 Mechanisms of molecular mimicry of plant CLE peptide ligands by the parasitic nematode Globodera rostochiensis. Plant physiology 64 21750229
2007 Diverse and conserved roles of CLE peptides. Current opinion in plant biology 64 18078779
2016 CLE Peptide Signaling and Crosstalk with Phytohormones and Environmental Stimuli. Frontiers in plant science 63 26779239
2019 Control of proliferation in the haploid meristem by CLE peptide signaling in Marchantia polymorpha. PLoS genetics 61 30845139
2009 CLE peptide signaling during plant development. Protoplasma 61 20016993
2016 Expression of the CLE-RS3 gene suppresses root nodulation in Lotus japonicus. Journal of plant research 60 27294965
2014 The soybean (Glycine max) nodulation-suppressive CLE peptide, GmRIC1, functions interspecifically in common white bean (Phaseolus vulgaris), but not in a supernodulating line mutated in the receptor PvNARK. Plant biotechnology journal 60 25040127
2006 CLE peptide ligands and their roles in establishing meristems. Current opinion in plant biology 60 17129751
2003 Epidemiology of reflux disease and CLE in East Asia. Journal of gastroenterology 55 12698867
2010 Regulation of vascular development by CLE peptide-receptor systems. Journal of integrative plant biology 54 20074136
2015 Enhanced resistance to soybean cyst nematode Heterodera glycines in transgenic soybean by silencing putative CLE receptors. Plant biotechnology journal 53 25581705
2018 CLE peptide tri-arabinosylation and peptide domain sequence composition are essential for SUNN-dependent autoregulation of nodulation in Medicago truncatula. The New phytologist 50 29393515
2013 Evolutionarily conserved CLE peptide signaling in plant development, symbiosis, and parasitism. Current opinion in plant biology 49 24035739
2021 WOX going on: CLE peptides in plant development. Current opinion in plant biology 47 34077886
2022 A Dof-CLE circuit controls phloem organization. Nature plants 46 35817820
2006 hCLE/CGI-99, a human protein that interacts with the influenza virus polymerase, is a mRNA transcription modulator. Journal of molecular biology 43 16950395
2014 Bioinformatic and phylogenetic analysis of the CLAVATA3/EMBRYO-SURROUNDING REGION (CLE) and the CLE-LIKE signal peptide genes in the Pinophyta. BMC plant biology 40 24529101
2008 Dual assay for MCLV3 activity reveals structure-activity relationship of CLE peptides. Biochemical and biophysical research communications 40 18848920
2013 A CLE-WOX signalling module regulates root meristem maintenance and vascular tissue development in rice. Journal of experimental botany 39 24043854
2013 Structure-function analysis of the GmRIC1 signal peptide and CLE domain required for nodulation control in soybean. Journal of experimental botany 38 23386683
2011 Cellular human CLE/C14orf166 protein interacts with influenza virus polymerase and is required for viral replication. Journal of virology 38 21900157
2009 Evolution of CLE signaling: origins of the CLV1 and SOL2/CRN receptor diversity. Plant signaling & behavior 37 19816140
2004 A novel ninein-interaction protein, CGI-99, blocks ninein phosphorylation by GSK3beta and is highly expressed in brain tumors. FEBS letters 37 15147888
2021 CLE peptides: critical regulators for stem cell maintenance in plants. Planta 36 34841457
2015 CLE peptide signaling in plants - the power of moving around. Physiologia plantarum 35 26096704
2010 Two CLE genes are induced by phosphate in roots of Lotus japonicus. Journal of plant research 34 20428922
2022 Evolution of meristem zonation by CLE gene duplication in land plants. Nature plants 33 35854003
2014 Nitrate inhibits soybean nodulation by regulating expression of CLE genes. Plant science : an international journal of experimental plant biology 33 25443828
2015 Antagonistic peptide technology for functional dissection of CLE peptides revisited. Journal of experimental botany 32 26136270
2020 Evolution of CLE peptide signalling. Seminars in cell & developmental biology 31 32444290
2019 CLE-CLAVATA1 Signaling Pathway Modulates Lateral Root Development under Sulfur Deficiency. Plants (Basel, Switzerland) 31 31003469
2018 Triarabinosylation is required for nodulation-suppressive CLE peptides to systemically inhibit nodulation in Pisum sativum. Plant, cell & environment 31 29722016
2017 CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling. Oncogene 29 28166202
2006 CLV3/ESR-related (CLE) peptides as intercellular signaling molecules in plants. Chemical record (New York, N.Y.) 29 17304552
2016 Identification and characterization of the Populus trichocarpa CLE family. BMC genomics 28 26935217
2017 Differential CLE peptide perception by plant receptors implicated from structural and functional analyses of TDIF-TDR interactions. PloS one 27 28384649
2020 Predicting and clustering plant CLE genes with a new method developed specifically for short amino acid sequences. BMC genomics 26 33045986
2014 CLE peptides regulate lateral root development in response to nitrogen nutritional status of plants. Plant signaling & behavior 26 25763500
2012 CLE signaling systems during plant development and nematode infection. Plant & cell physiology 26 23045524
2019 Identification and Functional Analysis of the CLAVATA3/EMBRYO SURROUNDING REGION (CLE) Gene Family in Wheat. International journal of molecular sciences 25 31484454
2015 The structure and activity of nodulation-suppressing CLE peptide hormones of legumes. Functional plant biology : FPB 25 32480669
2012 CLE peptides in plants: proteolytic processing, structure-activity relationship, and ligand-receptor interaction. Journal of integrative plant biology 25 22925455
2024 Antagonistic CLE peptide pathways shape root meristem tissue patterning. Nature plants 24 39468296
2011 Search for nodulation-related CLE genes in the genome of Glycine max. Journal of experimental botany 23 21273331
2024 The Role of CLE Peptides in the Suppression of Mycorrhizal Colonization of Tomato. Plant & cell physiology 21 37874980
2016 CLE peptide signaling and nitrogen interactions in plant root development. Plant molecular biology 21 26994997
2019 hCLE/RTRAF-HSPC117-DDX1-FAM98B: A New Cap-Binding Complex That Activates mRNA Translation. Frontiers in physiology 20 30833903
2013 CLE peptides in vascular development. Journal of integrative plant biology 20 23473393
2020 Nitrate-Induced CLE Peptide Systemically Inhibits Nodulation in Medicago truncatula. Plants (Basel, Switzerland) 19 33126720
2019 CLE-10 from Carpesium abrotanoides L. Suppresses the Growth of Human Breast Cancer Cells (MDA-MB-231) In Vitro by Inducing Apoptosis and Pro-Death Autophagy Via the PI3K/Akt/mTOR Signaling Pathway. Molecules (Basel, Switzerland) 19 30897708
2015 Sequence and Spatiotemporal Expression Analysis of CLE-Motif Containing Genes from the Reniform Nematode (Rotylenchulus reniformis Linford & Oliveira). Journal of nematology 19 26170479
2016 Identification, expression, and functional analysis of CLE genes in radish (Raphanus sativus L.) storage root. BMC plant biology 18 26821718
2022 Deeper genomic insights into tomato CLE genes repertoire identify new active peptides. BMC genomics 17 36396987
2021 Genome-wide identification of CLE gene family and their potential roles in bolting and fruit bearing in cucumber (Cucumis sativus L.). BMC plant biology 16 33740893
2021 Proteome study of cutaneous lupus erythematosus (CLE) and dermatomyositis skin lesions reveals IL-16 is differentially upregulated in CLE. Arthritis research & therapy 16 33931094
2019 Cytokinin and CLE signaling are highly intertwined developmental regulators across tissues and species. Current opinion in plant biology 16 31280129
2010 Variable domain I of nematode CLEs directs post-translational targeting of CLE peptides to the extracellular space. Plant signaling & behavior 16 21150256
2010 Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE. Immunogenetics 15 21132284
2023 A phosphoinositide hub connects CLE peptide signaling and polar auxin efflux regulation. Nature communications 14 36702874
2022 Spatial range, temporal span, and promiscuity of CLE-RLK signaling. Frontiers in plant science 14 36092449
2019 Genome-wide identification of the CLAVATA3/EMBRYO SURROUNDING REGION (CLE) family in grape (Vitis vinifera L.). BMC genomics 14 31277568
2019 CLE-HAR1 Systemic Signaling and NIN-Mediated Local Signaling Suppress the Increased Rhizobial Infection in the daphne Mutant of Lotus japonicus. Molecular plant-microbe interactions : MPMI 14 31880983
2013 Saccharification of recalcitrant biomass and integration options for lignocellulosic sugars from Catchlight Energy's sugar process (CLE Sugar). Biotechnology for biofuels 14 23356449
2012 Interaction of PTPIP51 with Tubulin, CGI-99 and Nuf2 During Cell Cycle Progression. Biomolecules 14 24970130
2023 Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - Part IV: the ECETOC and CLE Proposal for a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS). Critical reviews in toxicology 13 37554099
2020 Identification and comprehensive analysis of the CLV3/ESR-related (CLE) gene family in Brassica napus L. Plant biology (Stuttgart, Germany) 13 32223006
2023 Control of stem cell behavior by CLE-JINGASA signaling in the shoot apical meristem in Marchantia polymorpha. Current biology : CB 12 37977139
2023 Dairy Cow Mastitis Detection by Thermal Infrared Images Based on CLE-UNet. Animals : an open access journal from MDPI 11 37444009
2017 MicroRNA in Skeletal Muscle: Its Crucial Roles in Signal Proteins, Mus cle Fiber Type, and Muscle Protein Synthesis. Current protein & peptide science 11 27341987
2025 Ethylene-independent modulation of root development by ACC via downregulation of WOX5 and group I CLE peptide expression. Proceedings of the National Academy of Sciences of the United States of America 10 39908106
2024 Identification and Application of CLE Peptides for Drought Resistance in Solanaceae Crops. Journal of agricultural and food chemistry 10 38836320
2005 Functional characterization of the geminiviral conserved late element (CLE) in uninfected tobacco. Plant molecular biology 10 16021333

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