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Showing TNRC6A — TNRC6 is a alias.

TNRC6A

Trinucleotide repeat-containing gene 6A protein · UniProt Q8NDV7

Length
1962 aa
Mass
210.3 kDa
Annotated
2026-06-10
94 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNRC6A (GW182) is the central scaffold of the microRNA-induced silencing complex (miRISC), translating Argonaute-bound miRNA target recognition into translational repression and mRNA decay (PMID:16284623, PMID:16815998, PMID:22187428). Its N-terminal, intrinsically disordered region presents multiple GW/WG tryptophan motifs that dock into tryptophan-binding pockets on Argonaute proteins (AGO1-4); structural work on the hAgo1–GW182 hook interaction shows a single GW182-binding site per Ago, that miRNA loading raises Ago affinity for GW182, and that one GW182 molecule can engage up to three Ago copies (PMID:19383768, PMID:24043833, PMID:28781232). The C-terminal silencing domain is the effector module: it binds PABPC1 through a PAM2 motif (structurally defined against the PABPC1 Mlle/PABC domain) to disrupt mRNA circularization, and directly recruits the PAN2-PAN3 (via the PAN3 pseudokinase tryptophan pocket) and CCR4-NOT (via NOT1 and the CNOT9 subunit) deadenylase complexes through tryptophan-containing motifs, driving biphasic deadenylation followed by decapping and 5'→3' decay (PMID:19797087, PMID:21063388, PMID:20098421, PMID:21981923, PMID:23932717, PMID:35822830). Repression and decay are mechanistically coupled: GW182 also displaces PABP from targets in a CCR4-NOT-dependent, deadenylation-independent manner, and additionally bridges the 4EHP-GIGYF1/2 cap-dependent repression machinery (PMID:23172285, PMID:23463101, PMID:36854607). As the integral structural component of GW/P-bodies, TNRC6A organizes these cytoplasmic foci and stress granules, with localization controlled by Ago binding and nuclear-cytoplasmic shuttling via defined NES/NLS signals (PMID:15494374, PMID:23150874, PMID:26446993, PMID:37427791). Beyond cytoplasmic silencing, TNRC6A acts as a limiting hub shared among AGO2-, TRIM71-, and UPF1-dependent pathways, participates in nuclear RNA-mediated transcriptional regulation, and is itself regulated by TRIM65-mediated ubiquitination and by C-terminal serine phosphorylation that tunes CCR4-NOT binding (PMID:24778252, PMID:28813667, PMID:33668648, PMID:37369201). In vivo, gene-trap disruption in mouse yolk sac endoderm causes growth arrest and apoptosis with de-repression of miRNA targets, establishing TNRC6A as an essential functional component of miRISC (PMID:22187428).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 Medium

    Established TNRC6A/GW182 as a phosphorylated, mRNA-associated cytoplasmic protein, raising the question of its role in post-transcriptional regulation.

    Evidence Autoimmune serum immunoscreening, cDNA cloning, immunofluorescence, and mRNA co-IP defining GW-body localization

    PMID:11950943

    Open questions at the time
    • No mechanism for mRNA association
    • No link to silencing pathways yet
  2. 2004 Medium

    Showed GW182 is required to build GW/P-bodies and that these foci are dynamically regulated across the cell cycle, framing GW182 as a structural organizer rather than a passenger.

    Evidence siRNA knockdown with immunofluorescence and cell synchronization in human cells

    PMID:15494374

    Open questions at the time
    • Whether P-body integrity is required for silencing was unresolved
    • No molecular partners identified
  3. 2006 High

    Placed GW182 functionally downstream of Argonaute in the miRNA pathway and separated translational repression from mRNA decay, identifying CCR4-NOT and decapping as required for the decay arm only.

    Evidence Tethering, depletion, expression profiling, and N-terminal GW–AGO1 PIWI co-IP in Drosophila

    PMID:16177138 PMID:16284623 PMID:16815998

    Open questions at the time
    • Direct deadenylase recruitment contacts not yet mapped
    • Translational repression mechanism unknown
  4. 2008 High

    Defined the Ago–GW182 interface (conserved AGO phenylalanines) and showed GW182 represses even poly(A)-less reporters, establishing GW182 as an autonomous effector whose function extends beyond promoting deadenylation.

    Evidence AGO1 site-directed mutagenesis, depletion, and tethering reporter assays

    PMID:18345015 PMID:19056672

    Open questions at the time
    • Identity of repression effectors recruited by the C-terminal domain unknown
  5. 2009 High

    Resolved the bipartite architecture: N-terminal GW repeats bind all four Argonautes via multiple sites, while the C-terminal silencing domain independently drives repression and decay through PABPC1 binding and biphasic (PAN2-PAN3 then CCR4-CAF1) deadenylation.

    Evidence Deletion mapping, Co-IP, tethering, cell-free deadenylation, NMR of the RRM, and PABPC1 competition assays across paralogs and species

    PMID:19295135 PMID:19304925 PMID:19324964 PMID:19383768 PMID:19383769 PMID:19398495 PMID:19797087 PMID:19838187

    Open questions at the time
    • Atomic structures of deadenylase-recruiting contacts not yet determined
    • RRM ligand specificity undefined
  6. 2010 High

    Provided structural and mutational proof of the GW182–PABPC1 interaction (PAM2 motif against the PABC/Mlle domain) and showed it is essential for both silencing arms and for deadenylation.

    Evidence PAM2 point mutagenesis with reporter assays, X-ray crystallography of PABPC1 Mlle–GW182 peptide, and in vitro deadenylation

    PMID:20098421 PMID:20181956 PMID:21063388

    Open questions at the time
    • How PABP displacement is coordinated with deadenylase action not yet shown
  7. 2011 High

    Identified the direct deadenylase recruitment mechanism: GW182 contacts PAN3 and NOT1 directly, and tryptophan-containing W-motifs are the transferable repressive units that bind CCR4-NOT, demonstrated by reconstitution in a heterologous yeast polypeptide.

    Evidence Co-IP screens, deletion mapping, complementation, deadenylation assays, W-motif mutagenesis and heterologous engineering

    PMID:21981923 PMID:21984184

    Open questions at the time
    • Structural basis of W-motif recognition by deadenylase subunits not yet solved
  8. 2011 High

    Demonstrated GW182 is an essential in vivo miRISC component, with loss causing miRNA target de-repression, growth arrest, and apoptosis without changing miRNA abundance.

    Evidence Gene-trap mouse knockout with target de-repression and apoptosis analysis in yolk sac endoderm

    PMID:22187428

    Open questions at the time
    • Tissue-specific roles beyond yolk sac endoderm not addressed
  9. 2012 High

    Showed the PABP- and deadenylase-binding activities are jointly required for both repression and decay across species, and revealed nuclear-cytoplasmic shuttling that can carry Ago and silencing activity into the nucleus.

    Evidence Mutant functional assays in Drosophila and human cells; NES/NLS mutagenesis with fractionation and reporter assays

    PMID:23150874 PMID:23172285

    Open questions at the time
    • Functional significance of nuclear silencing in normal physiology unclear
  10. 2013 High

    Ordered the silencing steps mechanistically (PABP dissociation precedes deadenylation, driven by CCR4-NOT) and provided structural basis for PAN3 and a refined two-step Ago–tryptophan engagement model.

    Evidence Cap-binding complex IP under deadenylation block, depletion, tethering; X-ray crystallography of PAN3; NMR and cross-linking/MS of the Ago-binding domain

    PMID:23463101 PMID:23932717 PMID:24043833

    Open questions at the time
    • How disordered Ago-binding domain dynamics scale to full-length complex unresolved
  11. 2014 Medium

    Revealed regulation of GW182 stability by TRIM65-mediated ubiquitination, linking miRISC effector abundance to silencing strength.

    Evidence Proteomic screen, Co-IP, in vivo ubiquitination, and gain/loss-of-function reporter assays

    PMID:24778252

    Open questions at the time
    • Single lab; physiological signals controlling TRIM65 not defined
  12. 2017 High

    Defined the single high-affinity Ago hook interaction structurally (miRNA loading enhances GW182 affinity) and uncovered a nuclear interactome implicating TNRC6A in RNA-mediated transcriptional activation.

    Evidence X-ray crystallography of hAgo1–hook with binding measurements; nuclear-lysate mass spectrometry with Co-IP and transcriptional reporter validation; HDX/MS of the silencing domain

    PMID:28781232 PMID:28813667 PMID:29080206

    Open questions at the time
    • Mechanism of nuclear transcriptional activation incompletely defined
    • RRM dynamic role functionally untested in HDX study
  13. 2019 Medium

    Distinguished TNRC6A's pathway specificity (required for miRNA silencing and promoter-directed transcriptional activation but not for fully complementary siRNA silencing) and identified GW182 as a target hijacked by KSHV ORF57 to block P-body assembly.

    Evidence TNRC6A/B knockout cell lines across silencing pathways; Co-IP, live imaging, and viral titer measurement in KSHV-infected cells

    PMID:31400113 PMID:31670606

    Open questions at the time
    • Paralog-specific division of labor not fully mapped
  14. 2021 Medium

    Extended GW182 function to neuronal dendritic growth, extracellular-vesicle miRNA export, and identified an additional regulatory layer via C-terminal phosphorylation tuning CCR4-NOT binding and a Nup358 interaction relevant to ANE1 disease mutants.

    Evidence shRNA knockdown with morphometric and translation assays in neurons; EV isolation and miRNA measurement; phosphosite MS with phosphomimetic mutagenesis and Co-IP; Nup358 deletion/mutant Co-IP with reporter assays

    PMID:33668648 PMID:33685914 PMID:33962210 PMID:34328181

    Open questions at the time
    • Kinases/phosphatases controlling the phosphosites unidentified
    • Direct disease causation by Nup358–GW182 axis not established
  15. 2022 Medium

    Identified an additional CCR4-NOT (CNOT9) recruitment interface within the N-terminal Ago-binding domain, expanding the repertoire of GW182 deadenylase contacts.

    Evidence Co-IP with deletion constructs and tryptophan alanine-substitution mutagenesis

    PMID:35822830

    Open questions at the time
    • Single lab; quantitative contribution relative to C-terminal contacts unknown
  16. 2023 High

    Established TNRC6A as a limiting hub shared among AGO2-, TRIM71-, and UPF1-driven silencing, bridges 4EHP via GIGYF1/2, and contributes to stress-granule biogenesis, integrating it across multiple regulatory networks.

    Evidence Genetic epistasis and competition with RNA-seq; X-ray crystallography of GIGYF GYF–TNRC6 peptide; knockdown with live imaging of SG/PB

    PMID:36854607 PMID:37369201 PMID:37427791

    Open questions at the time
    • Cellular cues that partition limiting TNRC6 among competing pathways unknown
  17. 2024 Medium

    Demonstrated a target-stabilizing role for TNRC6A in vivo, where direct binding maintains miR-21-3p in cortical neurons to regulate CRF and anxiety-like behavior.

    Evidence RIP, RNA pulldown, in vivo knockdown with behavioral and molecular readouts in mouse prefrontal cortex

    PMID:39424169

    Open questions at the time
    • Generality of miRNA-stabilization function beyond miR-21-3p untested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the partitioning of limiting TNRC6A among competing AGO2/TRIM71/UPF1 pathways and between cytoplasmic silencing versus nuclear transcriptional roles is dynamically controlled in cells remains unresolved.
  • No upstream signaling logic identified for pathway choice
  • Physiological triggers for nuclear shuttling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 4 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 3 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
AGO1AGO2CNOT1CNOT9GIGYF2PABPC1PAN3TRIM65
Complex memberships
GW body/P-bodymiRISCstress granule

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GW182 (TNRC6A) is a phosphorylated cytoplasmic protein containing GW repeats and an RNA recognition motif that localizes to discrete cytoplasmic speckles (GW bodies) and associates with a subset of cellular mRNAs, suggesting a role in post-transcriptional regulation. Autoimmune serum immunoscreening, cDNA cloning, indirect immunofluorescence, mRNA co-immunoprecipitation Molecular biology of the cell Medium 11950943
2003 GW182 colocalizes with mRNA degradation factors hDcp1 and hLSm4 in cytoplasmic GW bodies, placing GW182 in the mRNA degradation pathway. Co-immunofluorescence microscopy with antibodies to hLSm4 and hDcp1 RNA (New York, N.Y.) Medium 13130130
2004 GW182 is a critical structural component of GW bodies; siRNA-mediated knockdown of GW182 causes disappearance of GW bodies. GW body number and size vary with cell cycle stage and proliferative status, with GW bodies disassembling prior to mitosis and reassembling in early G1. siRNA knockdown, immunofluorescence, cell synchronization with double-thymidine block, CENP-F/PCNA co-staining Journal of cell science Medium 15494374
2005 GW182 physically interacts with Argonaute proteins (AGO1-4) and is required for microRNA-mediated silencing; silencing of GW182 delocalizes P-body proteins and impairs miRNA reporter silencing. Mutations preventing Argonaute localization to P-bodies also prevent translational repression. Co-immunoprecipitation, siRNA knockdown, reporter assays, confocal microscopy Nature cell biology High 16284623
2005 GW182 and the DCP1:DCP2 decapping complex are both required for miRNA-mediated gene silencing in Drosophila cells, as depletion of either abolishes silencing of miRNA reporters. RNAi depletion in Drosophila S2 cells, miRNA reporter assays RNA (New York, N.Y.) High 16177138
2006 Drosophila GW182 functions downstream of AGO1 in the miRNA pathway; its N-terminal GW repeats interact with the PIWI domain of AGO1. When tethered to a reporter, GW182 silences expression via both translational repression and mRNA destabilization. mRNA degradation by GW182 or miRNAs requires both the CCR4-NOT deadenylase (CAF1, NOT1) and the DCP1:DCP2 decapping complex, but translational repression does not require these degradation factors. GW182 depletion, mRNA expression profiling, tethering assays, CAF1/NOT1/DCP1/DCP2 depletion, co-immunoprecipitation (N-terminal GW repeats with AGO1 PIWI domain) Genes & development High 16815998
2008 Human GW182/TNRC6A and its isoform TNGW1 function as translational repressors downstream of Ago2; tethering GW182 or TNGW1 to a 3'-UTR reporter strongly represses translation independently of Ago2, whereas Ago2-tethered repression is completely dependent on GW182/TNGW1. Tethering assays, siRNA knockdown, luciferase reporter assays Journal of cell science Medium 19056672
2008 AGO1 mutations at two conserved phenylalanine residues (predicted cap-binding residues) prevent AGO1 interaction with GW182 and miRNAs, abolishing silencing. Depletion of GW182 or overexpression of its AGO1-binding domain relieves silencing of all reporters including those lacking poly(A) tails, indicating GW182 function extends beyond promoting deadenylation. Site-directed mutagenesis of AGO1, GW182 depletion, tethering assays, reporter assays in Drosophila cells Nature structural & molecular biology High 18345015
2009 The N-terminal GW-repeat-containing regions of TNRC6A, TNRC6B, and TNRC6C each interact with all four human Argonaute proteins (AGO1-4), while the C-terminal silencing domains independently promote translational repression and mRNA deadenylation/degradation. Co-immunoprecipitation, tethering assays, deletion mapping, mRNA stability assays RNA (New York, N.Y.) High 19383768
2009 The C-terminal silencing domain of GW182 interacts with PABPC1, competing with eIF4G for PABPC1 binding. This interaction is required for both translational repression (by disrupting mRNA circularization) and mRNA degradation. GW182 dissociates from miRNA targets downstream of deadenylation, indicating it initiates but does not maintain silencing. Co-immunoprecipitation, tethering assays, PABPC1 overexpression rescue, deletion/mutagenesis analysis in Drosophila cells Molecular and cellular biology High 19797087
2009 Human GW182 contains three Argonaute-binding sites within the N-terminal GW/WG-repeated region; each site is individually sufficient for Ago2 binding, and multiple Ago proteins can be connected through a single GW182 molecule. A GW182 fragment containing the Ago-binding region partially relieves let-7-mediated repression and delays deadenylation in a mammalian cell-free system. Deletion mapping, GST pulldown, co-immunoprecipitation, mammalian cell-free translation/deadenylation assay RNA (New York, N.Y.) Medium 19398495
2009 The C-terminal half of human Ago2 binds to four non-overlapping GW-rich regions of GW182, and this interaction is required for Ago2 recruitment to GW bodies and for translational repression; the N-terminal half of Ago2 does not bind GW182 and lacks repression function. GST pulldown, GFP/Flag co-immunoprecipitation, deletion mapping, tethering assays, GW182 knockdown RNA (New York, N.Y.) Medium 19324964
2009 The C-terminal domain of TNRC6C (containing the RRM) is the key effector domain for translational repression; tethering of each human TNRC6 protein to a reporter mRNA dramatically inhibits protein synthesis through combined effects on mRNA level and translation. Tethering assays, deletion and mutagenesis analysis, reporter assays RNA (New York, N.Y.) Medium 19304925
2009 The GW182 RRM domain adopts a canonical RRM fold with an additional C-terminal alpha-helix that occludes the typical RNA-binding surface; the domain lacks general RNA-binding affinity but contributes to silencing activity in a miRNA target-specific manner through an exposed hydrophobic cleft. NMR structure determination, RNA-binding assays, deletion/mutation analysis in Drosophila cells, tethering assays Nucleic acids research High 19295135
2009 miRNA-mediated silencing requires the N-terminal AGO1-interaction domain of GW182 (through multiple GW repeats) AND the bipartite middle/C-terminal silencing domain; P-body localization is not required for silencing activity. Complementation assays with GW182 mutants in GW182-depleted Drosophila cells, co-immunoprecipitation, tethering assays RNA (New York, N.Y.) High 19383769
2009 Ago2 phenylalanines Phe470 and Phe505 are critical for recruiting TNRC6 (GW182) to promote deadenylation; TNRC6 tethering recapitulates biphasic deadenylation (Pan2-Pan3 followed by Ccr4-Caf1) leading to Dcp1-Dcp2-directed decapping. All four human Ago proteins and TNRC6C individually trigger this two-step deadenylation. Transcriptional pulsing, RNA tethering, dominant-negative mutant overexpression, siRNA knockdown, site-directed mutagenesis of Ago2 Nature structural & molecular biology High 19838187
2010 GW182 contains two PABPC1-binding sites: one containing a PAM2 motif (essential in human TNRC6A-C) and one in the M2/C-terminal silencing domain sequences. A single amino acid substitution in the TNRC6A PAM2 motif abolishes PABPC1 interaction and impairs silencing activity. Co-immunoprecipitation, PAM2 point mutagenesis, silencing reporter assays in Drosophila and human cells The EMBO journal High 21063388
2010 Crystal structure of the PABC (Mlle) domain of PABPC1 in complex with a peptide from GW182 (TNRC6C) reveals the molecular basis for GW182-PABPC1 interaction; mutations at the interface impair mRNA deadenylation in mammalian cell extracts. X-ray crystallography, mutagenesis, in vitro deadenylation assay in cell extracts Nature structural & molecular biology High 20098421
2010 Crystal structures of the PABPC1 Mlle domain in complex with peptides from GW182 (TNRC6C) and Ataxin-2 reveal overlapping but distinct binding sites with low to submicromolar affinity, providing structural basis for PABPC1 role in miRNA-mediated mRNA deadenylation. X-ray crystallography, mutagenesis, binding affinity measurements The Journal of biological chemistry High 20181956
2011 Human GW182 proteins directly recruit the PAN2-PAN3 and CCR4-CAF1-NOT deadenylase complexes through direct protein-protein interactions with PAN3 and NOT1 respectively; these interactions are critical for miRNA-mediated silencing and conserved in Drosophila. Co-immunoprecipitation screen, deletion mapping, complementation assays, deadenylation assays Molecular cell High 21981923
2011 The critical repressive features of both N-terminal and C-terminal effector domains of GW182 are G/S/TW or WG/S/T tryptophan-containing motifs that function additively to repress mRNA by recruiting components of the CCR4-NOT deadenylase complex; a heterologous yeast polypeptide with engineered WG/S/T motifs acquired CCR4-NOT binding and mRNA repression activity. Mutagenesis of W motifs, tethering assays, co-immunoprecipitation, heterologous domain engineering in yeast polypeptide Nature structural & molecular biology High 21984184
2012 TNRC6A is a nuclear-cytoplasmic shuttling protein with an identified nuclear export signal (NES) and nuclear localization signal (NLS); NES mutation causes nuclear retention. TNRC6A can recruit Ago proteins into the nucleus via its Ago-interacting motifs, where miRNAs also co-localize and retain gene silencing activity. NES/NLS mutagenesis, confocal microscopy, co-immunoprecipitation, nuclear fractionation, reporter silencing assays RNA (New York, N.Y.) Medium 23150874
2012 GW182 interactions with both PABP and deadenylases are required for miRNA-mediated translational repression AND mRNA degradation in Drosophila and human cells, indicating these two silencing mechanisms are mechanistically linked. Functional assays with GW182 mutants defective in PABP and/or deadenylase binding in Drosophila and human cells Nucleic acids research High 23172285
2012 GW182 knockdown reduces transfected miRNA-mimic half-lives and miRNA secretion via exosomes; the GW182 Δ12 domain (containing the Ago hook) restores miRNA stability. A 3'-5' exoribonuclease complex is responsible for miRNA degradation specifically when GW182 is knocked down. lentiviral shRNA knockdown, miRNA half-life measurements, immunoprecipitation, targeted siRNA screening EMBO reports Medium 23090477
2013 GW182 proteins cause dissociation of PABP from silenced miRNA targets independently of deadenylation; this requires interaction of GW182 with the CCR4-NOT complex. NOT1 and POP2 subunits of CCR4-NOT can themselves displace PABP from mRNA poly(A) tails. eIF4G dissociates as a consequence of deadenylation, but PABP dissociation precedes deadenylation. mRNA-protein association assays (Cap-binding complex IP), deadenylation-blocked conditions, GW182 and CCR4-NOT depletion, tethering assays The EMBO journal High 23463101
2013 Crystal structure of the PAN3 pseudokinase reveals a tryptophan-binding pocket at the homodimer interface that mediates binding to TNRC6C/GW182, providing the structural basis for PAN2-PAN3 recruitment to miRNA targets by TNRC6 proteins. X-ray crystallography, mutagenesis, in vivo mRNA degradation assays, co-immunoprecipitation Molecular cell High 23932717
2013 NMR and biochemical experiments show that only a subset of tryptophan residues in the intrinsically disordered AGO-binding domain of GW182 engage in Ago interactions; flanking residues mediate additional weak interactions. Cross-linking/mass spectrometry maps GW protein contacts with Ago2, supporting a two-step binding model involving sequential engagement of two tryptophans separated by a minimal 10-aa spacer. NMR spectroscopy, biochemical binding assays, cross-linking followed by mass spectrometry, structural modeling Proceedings of the National Academy of Sciences of the United States of America High 24043833
2014 TRIM65 is an E3 ubiquitin ligase that ubiquitinates TNRC6 (GW182) proteins, leading to their degradation; TRIM65 colocalizes with TNRC6 in P-body-like structures and its overexpression relieves miRNA-mediated suppression while knockdown enhances it. Proteomic screen, co-immunoprecipitation, in vivo ubiquitination assays, overexpression and knockdown functional studies Proceedings of the National Academy of Sciences of the United States of America Medium 24778252
2015 TNRC6A subcellular localization is substantially controlled by direct interaction with Ago proteins; Ago2 overexpression tethers TNRC6A in P-bodies through Ago-bound small RNAs, and TNRC6A localization affects its RNA silencing activity. Ago2 overexpression, confocal microscopy, co-immunoprecipitation, NLS/NES mutation analysis, reporter silencing assays Nucleic acids research Medium 26446993
2017 Crystal structure of hAgo1 in complex with the hook motif of hGW182 reveals a 'gate'-like interaction critical for GW182 docking into one of hAgo1's tryptophan-binding pockets. hAgo1 and hAgo2 each have a single GW182-binding site; miRNA binding increases Ago affinity for GW182; hGW182 can recruit up to three Ago copies via its three GW motifs. X-ray crystallography, binding affinity measurements, miRNA-binding assays, functional interaction mapping Molecular cell High 28781232
2017 Nuclear TNRC6A interacts with proteins involved in RNA degradation, RNAi, CCR4-NOT complex, mediator complex, and histone-modifying complexes; functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation in the nucleus. Mass spectrometry of purified nuclear lysates, co-immunoprecipitation validation, functional reporter assays for transcriptional activation Cell reports Medium 28813667
2017 HDX/MS analysis of the GW182 silencing domain reveals it is divided into a natively unstructured region (including the CCR4-NOT interacting motif 1) and a distinct dynamic RRM domain; the RRM has high structural dynamics allowing water penetration throughout the domain. Hydrogen-deuterium exchange mass spectrometry (HDX/MS) Journal of the American Society for Mass Spectrometry Medium 29080206
2019 KSHV ORF57 inhibits P-body formation by interacting with the N-terminal GW-domain of GW182, blocking GW182 scaffolding activity at the initial stage of P-body formation, thereby promoting viral replication; cells with reduced GW182 expression showed 100-fold higher KSHV virion production. Co-immunoprecipitation, time-lapse confocal microscopy, GW182 knockdown in KSHV-infected cells, viral titer measurement Nucleic acids research Medium 31400113
2019 TNRC6 expression is not required for gene silencing by fully complementary RNA duplexes (siRNA-like); TNRC6 is required for miRNA-mediated silencing. TNRC6A (but not TNRC6B) is specifically required for RNA-mediated transcriptional activation targeting gene promoters. TNRC6A can affect Dicer cytoplasmic vs. nuclear localization, but none of the TNRC6 paralogs are necessary for nuclear localization of AGO2. TNRC6A and TNRC6B single and double knockout cell lines, reporter assays for multiple silencing pathways, subcellular fractionation Nucleic acid therapeutics Medium 31670606
2021 The N-terminal region of Nup358 directly interacts with the C-terminal silencing domain of GW182/TNRC6A; ANE1-associated Nup358 mutants show reduced interaction with GW182, and the T585M ANE1 mutation compromises Nup358's function in the miRNA pathway. Co-immunoprecipitation with deletion constructs, mutagenesis of Nup358 ANE1 mutations, miRNA pathway reporter assays Biochemical and biophysical research communications Medium 33962210
2021 In neurons, GW182/TNRC6A expression peaks during the period of extensive dendritic growth; perturbation of GW182 during this temporal window reduces dendritic growth. GW182 modulates dendritic architecture by regulating global somatodendritic translation, actin cytoskeletal dynamics, and specifically LIMK1 expression. Immunofluorescence, shRNA knockdown in hippocampal neurons, morphometric analysis of dendritic arborization, translation reporter assays, western blotting for LIMK1 Journal of cell science Medium 34328181
2021 GW182 proteins restrict extracellular vesicle-mediated miRNA export in a GW body integrity-dependent manner; GW182B-dependent retardation of miRNA export is independent of the HuR-mediated auxiliary pathway. GW182 knockdown, extracellular vesicle isolation, miRNA measurement, P-body disruption Molecular and cellular biology Medium 33685914
2021 TNRC6A C-terminal region is phosphorylated at S1332 and S1346 in HeLa cells; dephosphorylation of these sites enhances TNRC6A interaction with the CCR4-NOT complex, while phosphorylation at S1616/S1691 suppresses this interaction. Mass spectrometry identification of phosphorylation sites, PhosphoSitePlus database cross-reference, phosphomimetic and phospho-null mutagenesis, co-immunoprecipitation Genes Medium 33668648
2022 A tryptophan-rich region within the N-terminal Ago-binding domain of human GW182/TNRC6A (between the two Ago-binding sites) can independently associate with the CCR4-NOT complex, specifically the CNOT9 subunit; multiple tryptophan residues in GW/WG motifs are required for this interaction. Co-immunoprecipitation with deletion constructs, alanine substitution mutagenesis of tryptophan residues Genes to cells : devoted to molecular & cellular mechanisms Medium 35822830
2023 Crystal structures of GIGYF1 and GIGYF2 GYF domains in complex with proline-rich sequences from TNRC6A and TNRC6C reveal how TNRC6 bridges 4EHP to Argonaute-miRNA complexes; the TNRC6 proline-rich motifs bind a conserved array of aromatic residues on the GYF domain surface. X-ray crystallography, binding assays RNA (New York, N.Y.) High 36854607
2023 GW182 (TNRC6) functions as a central hub shared among multiple mRNA silencing pathways: AGO2, TRIM71, and UPF1 each recruit TNRC6 to specific transcript sets; cellular TNRC6 levels are limiting such that loss of AGO-TNRC6 binding enhances TRIM71- and UPF1-dependent silencing through TNRC6. Genetic epistasis, competition assays, knockdown of pathway components, RNA-seq analysis of pathway-specific targets Molecular cell High 37369201
2023 GW182 promotes stress granule (SG) biogenesis by providing scaffolding activity for aggregation of SG components; GW182 is repurposed from P-bodies to SGs under arsenite stress, and is essential for PB formation. GW182 knockdown, live imaging, immunofluorescence, SG/PB marker analysis under stress conditions Nucleic acids research Medium 37427791
2024 TNRC6A directly binds miR-21-3p and maintains its stability in prefrontal cortex neurons; TNRC6A knockdown reduces miR-21-3p levels, de-represses CRF expression, and induces anxiety-like behavior. RNA immunoprecipitation, RNA pulldown, RT-qPCR, TNRC6A knockdown in mouse PFC, behavioral assays, dual luciferase assay Neuropharmacology Medium 39424169
2011 GW182 (Tnrc6a) is selectively expressed in yolk sac endoderm; gene trap disruption of GW182 in mice leads to growth arrest and apoptosis with de-repression of miRNA targets (Cdkn1a/p21, Cdkn1c/p27, Lats1, Lats2, Rb1, Bim, Pten) without altering miRNA levels, demonstrating GW182 is an essential functional component of miRISC in vivo. Gene trap mouse knockout, miRNA target de-repression analysis, apoptosis assays, miRNA level measurement The Journal of biological chemistry High 22187428

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes & development 737 16815998
2005 A role for the P-body component GW182 in microRNA function. Nature cell biology 513 16284623
2005 A crucial role for GW182 and the DCP1:DCP2 decapping complex in miRNA-mediated gene silencing. RNA (New York, N.Y.) 368 16177138
2008 GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay. Nature structural & molecular biology 319 18345015
2002 A phosphorylated cytoplasmic autoantigen, GW182, associates with a unique population of human mRNAs within novel cytoplasmic speckles. Molecular biology of the cell 294 11950943
2011 miRNA repression involves GW182-mediated recruitment of CCR4-NOT through conserved W-containing motifs. Nature structural & molecular biology 291 21984184
2011 GW182 proteins directly recruit cytoplasmic deadenylase complexes to miRNA targets. Molecular cell 289 21981923
2003 The GW182 protein colocalizes with mRNA degradation associated proteins hDcp1 and hLSm4 in cytoplasmic GW bodies. RNA (New York, N.Y.) 220 13130130
2007 Systematic identification of C. elegans miRISC proteins, miRNAs, and mRNA targets by their interactions with GW182 proteins AIN-1 and AIN-2. Molecular cell 199 18042455
2004 GW182 is critical for the stability of GW bodies expressed during the cell cycle and cell proliferation. Journal of cell science 171 15494374
2012 Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus. RNA (New York, N.Y.) 160 23150874
2009 Ago-TNRC6 triggers microRNA-mediated decay by promoting two deadenylation steps. Nature structural & molecular biology 159 19838187
2009 The GW182 protein family in animal cells: new insights into domains required for miRNA-mediated gene silencing. RNA (New York, N.Y.) 151 19535464
2009 The silencing domain of GW182 interacts with PABPC1 to promote translational repression and degradation of microRNA targets and is required for target release. Molecular and cellular biology 137 19797087
2009 The C-terminal domains of human TNRC6A, TNRC6B, and TNRC6C silence bound transcripts independently of Argonaute proteins. RNA (New York, N.Y.) 119 19383768
2009 The C-terminal half of human Ago2 binds to multiple GW-rich regions of GW182 and requires GW182 to mediate silencing. RNA (New York, N.Y.) 115 19324964
2009 Importance of the C-terminal domain of the human GW182 protein TNRC6C for translational repression. RNA (New York, N.Y.) 106 19304925
2009 Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins. The EMBO journal 103 19131968
2009 Mammalian GW182 contains multiple Argonaute-binding sites and functions in microRNA-mediated translational repression. RNA (New York, N.Y.) 102 19398495
2010 Somatic mutations and losses of expression of microRNA regulation-related genes AGO2 and TNRC6A in gastric and colorectal cancers. The Journal of pathology 101 20198652
2013 The role of GW182 proteins in miRNA-mediated gene silencing. Advances in experimental medicine and biology 100 23224969
2009 A C-terminal silencing domain in GW182 is essential for miRNA function. RNA (New York, N.Y.) 96 19383769
2007 GW182 family proteins are crucial for microRNA-mediated gene silencing. Trends in cell biology 93 17766119
2013 GW182 proteins cause PABP dissociation from silenced miRNA targets in the absence of deadenylation. The EMBO journal 90 23463101
2013 Structural features of Argonaute-GW182 protein interactions. Proceedings of the National Academy of Sciences of the United States of America 89 24043833
2012 The interactions of GW182 proteins with PABP and deadenylases are required for both translational repression and degradation of miRNA targets. Nucleic acids research 89 23172285
2009 Functional dissection of the human TNRC6 (GW182-related) family of proteins. Molecular and cellular biology 87 19470757
2013 Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Molecular cell 84 23932717
2010 Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation. Nature structural & molecular biology 83 20098421
2010 Two PABPC1-binding sites in GW182 proteins promote miRNA-mediated gene silencing. The EMBO journal 83 21063388
2017 Multivalent Recruitment of Human Argonaute by GW182. Molecular cell 79 28781232
2010 Structural basis of binding of P-body-associated proteins GW182 and ataxin-2 by the Mlle domain of poly(A)-binding protein. The Journal of biological chemistry 78 20181956
2010 Role of GW182 proteins and PABPC1 in the miRNA pathway: a sense of déjà vu. Nature reviews. Molecular cell biology 74 20379206
2014 TRIM65 regulates microRNA activity by ubiquitination of TNRC6. Proceedings of the National Academy of Sciences of the United States of America 69 24778252
2008 Localization of double-stranded small interfering RNA to cytoplasmic processing bodies is Ago2 dependent and results in up-regulation of GW182 and Argonaute-2. Molecular biology of the cell 59 18946079
2003 Clinical and serological associations of autoantibodies to GW bodies and a novel cytoplasmic autoantigen GW182. Journal of molecular medicine (Berlin, Germany) 59 14598044
2013 Argonaute and GW182 proteins: an effective alliance in gene silencing. Biochemical Society transactions 52 23863144
2008 Identification of GW182 and its novel isoform TNGW1 as translational repressors in Ago2-mediated silencing. Journal of cell science 51 19056672
2013 Autophagy modulates miRNA-mediated gene silencing and selectively degrades AIN-1/GW182 in C. elegans. EMBO reports 48 23619095
2012 The Caenorhabditis elegans GW182 protein AIN-1 interacts with PAB-1 and subunits of the PAN2-PAN3 and CCR4-NOT deadenylase complexes. Nucleic acids research 44 22402495
2012 Defining a new role of GW182 in maintaining miRNA stability. EMBO reports 43 23090477
2009 The RRM domain in GW182 proteins contributes to miRNA-mediated gene silencing. Nucleic acids research 41 19295135
2013 Ethanol facilitates hepatitis C virus replication via up-regulation of GW182 and heat shock protein 90 in human hepatoma cells. Hepatology (Baltimore, Md.) 40 22898980
2013 GW182 controls Drosophila circadian behavior and PDF-receptor signaling. Neuron 40 23583112
2017 Human GW182 Paralogs Are the Central Organizers for RNA-Mediated Control of Transcription. Cell reports 38 28813667
2015 Control of the localization and function of a miRNA silencing component TNRC6A by Argonaute protein. Nucleic acids research 35 26446993
2010 Immunohistochemical analysis of RNA-induced silencing complex-related proteins AGO2 and TNRC6A in prostate and esophageal cancers. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 35 20402672
2017 miR-26a-5p Regulates TNRC6A Expression and Facilitates Theca Cell Proliferation in Chicken Ovarian Follicles. DNA and cell biology 32 28876086
2010 Divergent GW182 functional domains in the regulation of translational silencing. Nucleic acids research 30 21131274
2019 KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182. Nucleic acids research 28 31400113
2010 The GW/WG repeats of Drosophila GW182 function as effector motifs for miRNA-mediated repression. Nucleic acids research 27 20530530
2018 Role of GW182 protein in the cell. The international journal of biochemistry & cell biology 25 29791863
2003 A panel of monoclonal antibodies to cytoplasmic GW bodies and the mRNA binding protein GW182. Hybridoma and hybridomics 25 12831532
2023 RNA helicase DDX6 and scaffold protein GW182 in P-bodies promote biogenesis of stress granules. Nucleic acids research 24 37427791
2009 Optimization of immunoprecipitation-western blot analysis in detecting GW182-associated components of GW/P bodies. Nature protocols 24 19373232
2019 RIP-Chip analysis supports different roles for AGO2 and GW182 proteins in recruiting and processing microRNA targets. BMC bioinformatics 20 30999843
2013 Function of GW182 and GW bodies in siRNA and miRNA pathways. Advances in experimental medicine and biology 20 23224966
2019 Expression of TNRC6 (GW182) Proteins Is Not Necessary for Gene Silencing by Fully Complementary RNA Duplexes. Nucleic acid therapeutics 19 31670606
2018 The Requirement for GW182 Scaffolding Protein Depends on Whether Argonaute Is Mediating Translation, Transcription, or Splicing. Biochemistry 19 30086238
2021 Circular RNA CircCDYL Regulates Proliferation and Apoptosis in Non-Small Cell Lung Cancer Cells by Sponging miR-185-5p and Upregulating TNRC6A. Cancer management and research 18 33531835
2015 Early origin and adaptive evolution of the GW182 protein family, the key component of RNA silencing in animals. RNA biology 16 26106978
2017 Structural Dynamics of the GW182 Silencing Domain Including its RNA Recognition motif (RRM) Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry. Journal of the American Society for Mass Spectrometry 15 29080206
2023 Convergence of multiple RNA-silencing pathways on GW182/TNRC6. Molecular cell 14 37369201
2023 Consequences of depleting TNRC6, AGO, and DROSHA proteins on expression of microRNAs. RNA (New York, N.Y.) 13 37169394
2020 DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A. Journal of human genetics 13 33040085
2019 TNRC6 proteins modulate hepatitis C virus replication by spatially regulating the binding of miR-122/Ago2 complexes to viral RNA. Nucleic acids research 12 30997501
2016 IMP-3 protects the mRNAs of cyclins D1 and D3 from GW182/AGO2-dependent translational repression. International journal of oncology 12 27840950
2021 GW182 Proteins Restrict Extracellular Vesicle-Mediated Export of MicroRNAs in Mammalian Cancer Cells. Molecular and cellular biology 11 33685914
2017 Comprehensive Identification of Nuclear and Cytoplasmic TNRC6A-Associating Proteins. Journal of molecular biology 11 28478284
2010 Ago2 and GW182 expression in mouse preimplantation embryos: a link between microRNA biogenesis and GW182 protein synthesis. Reproduction, fertility, and development 11 20353723
2021 Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA function. Biochemical and biophysical research communications 10 33962210
2017 Dcp1a and GW182 Induce Distinct Cellular Aggregates and Have Different Effects on microRNA Pathway. DNA and cell biology 10 28488892
2010 The decapping activator HPat a novel factor co-purifying with GW182 from Drosophila cells. RNA biology 10 20458171
2023 Hypoxic BMSC-derived exosomal miR-652-3p promotes proliferation and metastasis of hepatocarcinoma cancer cells via targeting TNRC6A. Aging 9 37976119
2021 Downregulation of Long Noncoding RNA LINC00261 Attenuates Myocardial Infarction through the miR-522-3p/Trinucleotide Repeat-Containing Gene 6a (TNRC6A) Axis. Cardiovascular therapeutics 9 34239606
2015 Roles of mRNA fate modulators Dhh1 and Pat1 in TNRC6-dependent gene silencing recapitulated in yeast. The Journal of biological chemistry 8 25657010
2011 Mapping of Ago2-GW182 functional interactions. Methods in molecular biology (Clifton, N.J.) 8 21528446
2011 Trinucleotide repeat containing 6a (Tnrc6a)-mediated microRNA function is required for development of yolk sac endoderm. The Journal of biological chemistry 8 22187428
2019 Aberrant expression of TNRC6a and miR-21 during myocardial infarction. 3 Biotech 7 31245249
2023 Molecular basis for GIGYF-TNRC6 complex assembly. RNA (New York, N.Y.) 5 36854607
2021 Distinct temporal expression of the GW182 paralog TNRC6A in neurons regulates dendritic arborization. Journal of cell science 5 34328181
2023 LINC01082 Inhibits Non-Small Cell Lung Cancer by Targeting the miR-543/TNRC6A Axis. Biochemical genetics 4 36719626
2013 An SNP in the trinucleotide repeat region of the TNRC6A gene maps to a major TNGW1 autoepitope in patients with autoantibodies to GW182. Advances in experimental medicine and biology 3 23224974
2011 Continuous density gradients to study Argonaute and GW182 complexes associated with the endocytic pathway. Methods in molecular biology (Clifton, N.J.) 3 21528447
2011 An efficient system for let-7 microRNA and GW182 protein-mediated deadenylation in vitro. Methods in molecular biology (Clifton, N.J.) 3 21528456
2025 Mechanism of LncRNA NORAD/MiR-144-3p Axis in Promoting Myocardial Ischemia-Reperfusion Injury by Targeting TNRC6A. International heart journal 2 41034031
2024 miRNA-mediated gene silencing in Drosophila larval development involves GW182-dependent and independent mechanisms. The EMBO journal 2 39322759
2024 Prefrontal TNRC6A mediates anxiety-like behaviour by regulating CRF through the maintenance of miR-21-3p stability. Neuropharmacology 2 39424169
2022 MiR-652-3p promotes malignancy and metastasis of cancer cells via inhibiting TNRC6A in hepatocellular carcinoma. Biochemical and biophysical research communications 2 36495604
2021 Identification of Phosphorylated Amino Acids in Human TNRC6A C-Terminal Region and Their Effects on the Interaction with the CCR4-NOT Complex. Genes 2 33668648
2025 m5C modification of LINC01082 inhibits osteosarcoma progression by modulating the miR-543-TNRC6A axis. Translational oncology 1 40818239
2022 N-terminal Ago-binding domain of GW182 contains a tryptophan-rich region that confer binding to the CCR4-NOT complex. Genes to cells : devoted to molecular & cellular mechanisms 1 35822830
2026 LncRNA DLEU1 Regulates TNRC6A Expression to Exacerbate Acute Myocardial Infarction by Adsorbing miR-23a-3p. Journal of biochemical and molecular toxicology 0 42116800
2023 Circular RNA CircCDYL Regulates Proliferation and Apoptosis in Non-Small Cell Lung Cancer Cells by Sponging miR-185-5p and Upregulating TNRC6A [Retraction]. Cancer management and research 0 37465084

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