{"gene":"TARBP2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2009,"finding":"TARBP2 frameshift mutations in microsatellite-instable carcinomas cause diminished TRBP protein expression, defective miRNA processing, and destabilization of DICER1 protein; reintroduction of TRBP restores miRNA production and inhibits tumor growth.","method":"Mutational analysis, western blot, miRNA processing assays, rescue experiments in cancer cell lines","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutational sequencing, protein expression, functional miRNA processing assay, rescue experiment) replicated across tumor types","pmids":["19219043"],"is_preprint":false},{"year":2014,"finding":"TARBP2 knockout alters Dicer processing sites in a subset of miRNAs but does not affect Dicer stability, overall miRNA abundance, or Argonaute loading; TRBP and PACT do not functionally compensate for one another, and only TRBP contributes to Dicer processing accuracy.","method":"CRISPR/Cas9 knockout of TARBP2 and PACT in human cells, small RNA sequencing, western blot for Dicer and Ago2","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (sequencing, protein stability assays), single lab but rigorous controls including double-KO","pmids":["25437560"],"is_preprint":false},{"year":2014,"finding":"TARBP2 is hyperphosphorylated by JNK during M phase when PKR is activated by cellular dsRNAs; hyperphosphorylation potentiates TARBP2's inhibitory activity on PKR, suppressing PKR during M-G1 transition.","method":"TARBP2 knockout cells, JNK inhibitor treatment, phosphorylation assays, PKR activity measurements across cell cycle phases","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and biochemical kinase assays, multiple orthogonal methods in single rigorous study","pmids":["25437560"],"is_preprint":false},{"year":2014,"finding":"TARBP2 binds GC-rich structural cis-regulatory elements (TBSEs/sRSEs) in metastasis-suppressor mRNAs (APP and ZNF395) via its dsRNA-binding activity, destabilizing those transcripts to promote breast cancer invasion and metastasis.","method":"Whole-genome transcript stability measurements, RNA pull-down/biochemical binding assays, computational structure prediction, loss-of-function and rescue experiments in breast cancer cell lines, in vivo colonization assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transcript stability profiling, biochemical binding, in vivo models), single lab but comprehensive mechanistic follow-up","pmids":["25043050"],"is_preprint":false},{"year":2015,"finding":"TARBP2 is SUMOylated at K52; SUMOylation is enhanced by phosphorylation, stabilizes TARBP2 by repressing K48-linked ubiquitination, recruits Ago2 to form the RISC-loading complex (RLC), promotes pre-miRNA loading into the RLC, and stabilizes Ago2, thereby enhancing miRNA/siRNA efficiency.","method":"Site-directed mutagenesis (K52R), in vivo SUMOylation assays, Co-IP for Ago2 and Dicer, ubiquitination assays, RNAi reporter assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — active-site mutagenesis plus Co-IP and functional reporter assays, multiple orthogonal methods in single study","pmids":["26582366"],"is_preprint":false},{"year":2019,"finding":"Nuclear TARBP2 binds pre-mRNAs and recruits m6A RNA methylation machinery, leading to deposition of m6A marks that inhibit efficient splicing and cause intron retention; TARBP2 then interacts with the nucleoprotein TPR to promote degradation of bound transcripts by the nuclear exosome, destabilizing target mRNAs including ABCA3 and FOXN3.","method":"RNA-protein binding assays, m6A methylation assays, Co-IP with TPR, nuclear fractionation, RNA-seq for intron retention, xenograft mouse models, TARBP2 overexpression/knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods (m6A assay, Co-IP, RNA-seq) plus in vivo validation, single lab but comprehensive mechanistic study","pmids":["31300274"],"is_preprint":false},{"year":2018,"finding":"TARBP2 interacts with MAVS and disrupts MAVS-RIG-I and MAVS-TRAF3 associations, thereby negatively regulating virus-induced IFN-β production and innate antiviral response.","method":"Co-immunoprecipitation, overexpression and knockdown in 293T cells, IFN-β reporter assays, viral infection assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional reporter assays in single lab, moderate mechanistic follow-up","pmids":["30390472"],"is_preprint":false},{"year":2019,"finding":"TARBP2 inhibits IRF7-mediated IFN-β production by impairing TRAF6-mediated K63-linked ubiquitination of IRF7 (a prerequisite for IRF7 phosphorylation); TARBP2 also destabilizes endogenous TRAF6 and participates in the IRF7-TRAF6 interaction.","method":"Co-IP, ubiquitination assays, phosphorylation assays, overexpression in 293T cells, Sendai virus infection","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assays in single lab, two orthogonal biochemical methods","pmids":["30927622"],"is_preprint":false},{"year":2019,"finding":"TARBP2 protein is destabilized through autophagic-lysosomal proteolysis in sorafenib-resistant HCC cells; this TARBP2 loss stabilizes Nanog protein (a CSC marker), facilitating sorafenib resistance in a miRNA-independent manner.","method":"Lysosomal inhibitor treatment, protein stability assays, western blot, knockdown/overexpression in HCC cell lines","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitor plus protein stability assay, single lab, two orthogonal approaches","pmids":["30657254"],"is_preprint":false},{"year":2019,"finding":"Tamoxifen post-transcriptionally stabilizes TARBP2 protein through downregulation of Merlin, a TARBP2-interacting protein that enhances its proteasomal degradation; stabilized TARBP2 further stabilizes SOX2 protein, inducing tamoxifen resistance in ER+ breast cancer cells.","method":"Co-IP for Merlin-TARBP2 interaction, proteasomal inhibitor treatment, overexpression and knockdown in breast cancer cell lines, protein stability assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus pharmacological and genetic perturbation, single lab","pmids":["30759864"],"is_preprint":false},{"year":2021,"finding":"TARBP2 physically interacts with the stem-loop structures in the 3'UTRs of antiangiogenic factor mRNAs (THBS1/2, TIMP1, SERPINF1) via its dsRNA-binding domains 1/2, leading to mRNA destabilization and promotion of tumor angiogenesis.","method":"RNA immunoprecipitation, 3'UTR reporter assays, mRNA stability assays, TARBP2 domain deletion analysis, in vitro and in vivo angiogenesis assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain-deletion binding assay combined with functional mRNA stability and reporter assays, single lab","pmids":["33484209"],"is_preprint":false},{"year":2021,"finding":"TARBP2 suppresses proteasomal degradation of HIF-1α in breast cancer by downregulating multiple HIF-1α-targeting E3 ligases (VHL, FBXW7, TRAF6) and reducing HIF-1α ubiquitination, thereby maintaining HIF-1α protein stability under normoxia and hypoxia.","method":"Proteasome inhibitor treatment, ubiquitination assays, western blot for E3 ligases, TARBP2 overexpression/knockdown in breast cancer cells, IHC","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ubiquitination assay plus pharmacological and genetic perturbation, single lab","pmids":["35008634"],"is_preprint":false},{"year":2021,"finding":"Loss of TARBP2 reduces processing of miR-145, leading to upregulation of its target SERPINE1 (PAI-1), which promotes HCC cell proliferation, migration, and invasion; overexpression of miR-145 rescues the TARBP2-loss phenotype.","method":"shRNA knockdown, RNA-seq, luciferase reporter assay for miR-145/SERPINE1 interaction, rescue experiments in HCC cell lines","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay plus rescue epistasis experiment, single lab, two orthogonal methods","pmids":["34249676"],"is_preprint":false},{"year":2022,"finding":"TARBP2 binds SNHG7 lncRNA as an RNA-binding protein, increasing SNHG7 half-life (transcript stabilization); this TARBP2-SNHG7 interaction leads to sequestration of miR-17-5p, derepression of NFATC3, and increased blood-brain barrier permeability in an Aβ microenvironment.","method":"RNA immunoprecipitation, mRNA half-life assay, overexpression/knockdown in endothelial cells, luciferase reporter assay","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and stability assay without rigorous mechanistic dissection of TARBP2 binding domain","pmids":["35562351"],"is_preprint":false},{"year":2022,"finding":"TARBP2 interacts with LINC01526 lncRNA and is recruited by LINC01526 to degrade GNG7 mRNA, promoting gastric cancer proliferation and migration.","method":"RNA pull-down, Co-IP, mRNA stability assay, rescue experiments in gastric cancer cells, xenograft mouse model","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pulldown plus functional assay without mechanistic domain mapping","pmids":["36230863"],"is_preprint":false},{"year":2001,"finding":"The TARBP2 gene has two adjacent promoters driving alternative first exons for TRBP1 and TRBP2 isoforms; TRBP2 transcription and translation start sites are located within the first intron of TRBP1; promoter activity is specifically repressed in human astrocytic cells compared to HeLa cells.","method":"Gene isolation and sequencing, promoter deletion analysis, reporter assays, 5' RACE","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion analysis with reporter assays across multiple cell lines, single lab","pmids":["11641396"],"is_preprint":false}],"current_model":"TARBP2 (TRBP) is a multifunctional dsRNA-binding protein that acts as a DICER1 cofactor to fine-tune miRNA processing site selection and stabilize DICER1 protein; it is SUMOylated (at K52) to facilitate RISC-loading complex assembly with Ago2; it undergoes JNK-mediated hyperphosphorylation in M phase to inhibit PKR and permit M-G1 transition; in the nucleus it recruits m6A methylation machinery and the nucleoprotein TPR to promote intron retention and exosome-mediated degradation of target pre-mRNAs; in the cytoplasm it directly binds structural elements (TBSEs) in the 3'UTRs of metastasis-suppressor and antiangiogenic mRNAs to destabilize them; and it negatively regulates innate antiviral signaling by disrupting MAVS-RIG-I/TRAF3 complexes and suppressing TRAF6-mediated K63-ubiquitination of IRF7."},"narrative":{"mechanistic_narrative":"TARBP2 (TRBP) is a multifunctional double-stranded RNA-binding protein that operates in both miRNA biogenesis and direct sequence-specific control of mRNA stability across cancer, cell cycle, and innate immune contexts [PMID:19219043, PMID:25043050]. As a DICER1 cofactor, TARBP2 stabilizes DICER1 protein and is required for accurate Dicer cleavage-site selection on a subset of pre-miRNAs; loss-of-function frameshift mutations in microsatellite-instable carcinomas diminish TRBP, destabilize DICER1, and impair miRNA processing, while genetic knockout shifts Dicer processing sites without abolishing global miRNA abundance or Argonaute loading, an activity not shared with its paralog PACT [PMID:19219043, PMID:25437560]. SUMOylation at K52 stabilizes TARBP2 by repressing K48-linked ubiquitination and recruits Ago2 to assemble the RISC-loading complex, thereby enhancing small-RNA silencing efficiency [PMID:26582366]. Independent of miRNAs, cytoplasmic TARBP2 binds GC-rich structural elements (TBSEs) in the 3'UTRs of metastasis-suppressor (APP, ZNF395) and antiangiogenic (THBS1/2, TIMP1, SERPINF1) transcripts via its dsRNA-binding domains to destabilize them, promoting invasion, metastasis, and tumor angiogenesis [PMID:25043050, PMID:33484209]. In the nucleus, TARBP2 binds pre-mRNAs, recruits the m6A methylation machinery to drive intron retention, and engages the nucleoprotein TPR to target the modified transcripts for nuclear exosome degradation [PMID:31300274]. During M phase TARBP2 is hyperphosphorylated by JNK, potentiating its inhibition of PKR to permit the M-G1 transition [PMID:25437560], and it negatively regulates antiviral signaling by disrupting MAVS-RIG-I/TRAF3 complexes and impairing TRAF6-mediated K63-ubiquitination of IRF7 [PMID:30390472, PMID:30927622]. TARBP2 protein levels are themselves tightly controlled by proteasomal and autophagic-lysosomal turnover, with the interactor Merlin promoting its degradation [PMID:30657254, PMID:30759864].","teleology":[{"year":2001,"claim":"Established the genomic architecture of the TARBP2 locus, showing two adjacent promoters generate TRBP1/TRBP2 isoforms with cell-type-specific promoter regulation.","evidence":"Gene isolation, promoter deletion/reporter assays and 5' RACE across HeLa and astrocytic cells","pmids":["11641396"],"confidence":"Medium","gaps":["Functional consequences of isoform choice not defined","Mechanism of astrocyte-specific repression unknown"]},{"year":2009,"claim":"Linked TARBP2 to tumor suppression by showing its frameshift mutation impairs DICER1 stability and miRNA processing, addressing how miRNA biogenesis fails in microsatellite-instable cancers.","evidence":"Mutational analysis, western blot, miRNA processing and rescue assays in cancer cell lines","pmids":["19219043"],"confidence":"High","gaps":["Did not resolve which specific miRNAs drive the tumor phenotype","Mechanism of DICER1 stabilization by TRBP not detailed"]},{"year":2014,"claim":"Refined the DICER1 cofactor role by demonstrating TARBP2 governs Dicer processing-site accuracy rather than Dicer stability or global miRNA output, and is non-redundant with PACT.","evidence":"CRISPR/Cas9 single and double knockout, small RNA sequencing, western blot in human cells","pmids":["25437560"],"confidence":"High","gaps":["Apparent discrepancy with 2009 DICER1 stability finding not reconciled","Determinants of which miRNAs require TRBP for accuracy unknown"]},{"year":2014,"claim":"Defined a cell-cycle role: JNK hyperphosphorylates TARBP2 in M phase to potentiate PKR inhibition, answering how PKR is restrained during M-G1 transition.","evidence":"Knockout cells, JNK inhibitor, phosphorylation and PKR activity assays across cell cycle","pmids":["25437560"],"confidence":"High","gaps":["Phosphosites mediating PKR inhibition not mapped","Identity of the M-phase dsRNAs activating PKR unclear"]},{"year":2014,"claim":"Revealed a miRNA-independent function in which TARBP2 directly binds structural 3'UTR elements to destabilize metastasis-suppressor mRNAs, explaining a pro-metastatic role.","evidence":"Transcript stability profiling, RNA binding assays, structure prediction, in vivo colonization assays in breast cancer cells","pmids":["25043050"],"confidence":"High","gaps":["Decay machinery recruited by cytoplasmic TARBP2 not identified","Full target repertoire beyond APP/ZNF395 incomplete"]},{"year":2015,"claim":"Identified SUMOylation at K52 as a regulatory switch that stabilizes TARBP2 and recruits Ago2 for RISC-loading complex assembly, connecting post-translational modification to silencing efficiency.","evidence":"K52R mutagenesis, in vivo SUMOylation, Co-IP, ubiquitination and RNAi reporter assays","pmids":["26582366"],"confidence":"High","gaps":["SUMO ligase responsible not identified","Quantitative contribution of SUMOylation to physiological silencing unclear"]},{"year":2018,"claim":"Extended TARBP2 to innate immunity by showing it disrupts MAVS-RIG-I/TRAF3 complexes to dampen IFN-β production.","evidence":"Co-IP, overexpression/knockdown in 293T, IFN-β reporter and viral infection assays","pmids":["30390472"],"confidence":"Medium","gaps":["Single overexpression system without endogenous validation","Direct binding interface with MAVS not mapped"]},{"year":2019,"claim":"Defined a nuclear pathway in which TARBP2 recruits m6A machinery and TPR to drive intron retention and exosome-mediated decay of pre-mRNAs, establishing a chromatin-proximal mode of gene control.","evidence":"RNA-protein binding, m6A assays, Co-IP with TPR, intron-retention RNA-seq, xenograft models","pmids":["31300274"],"confidence":"High","gaps":["Which m6A writer subunit TARBP2 contacts not specified","Signals partitioning TARBP2 between nucleus and cytoplasm unknown"]},{"year":2019,"claim":"Showed TARBP2 inhibits IRF7-driven IFN-β by impairing TRAF6-mediated K63-ubiquitination of IRF7 and destabilizing TRAF6, broadening its antiviral suppressor role.","evidence":"Co-IP, ubiquitination and phosphorylation assays, Sendai virus infection in 293T","pmids":["30927622"],"confidence":"Medium","gaps":["Endogenous physiological context limited to overexpression system","Relationship to the MAVS-disruption mechanism not integrated"]},{"year":2019,"claim":"Demonstrated TARBP2 protein abundance is set by competing turnover routes (autophagic-lysosomal and Merlin-promoted proteasomal degradation), with miRNA-independent downstream effects on Nanog and SOX2 in drug resistance.","evidence":"Lysosomal/proteasomal inhibitors, Co-IP for Merlin, protein stability assays in HCC and breast cancer lines","pmids":["30657254","30759864"],"confidence":"Medium","gaps":["Mechanism by which TARBP2 stabilizes Nanog/SOX2 not defined","In vivo relevance of these turnover routes not established"]},{"year":2021,"claim":"Expanded the cytoplasmic mRNA-destabilization role to antiangiogenic transcripts and miR-145 processing, and revealed TARBP2 control of HIF-1α stability via E3 ligase downregulation.","evidence":"RIP, 3'UTR reporter and stability assays, domain deletion, miR-145 rescue, ubiquitination assays in cancer cells and xenografts","pmids":["33484209","34249676","35008634"],"confidence":"Medium","gaps":["Whether HIF-1α and angiogenesis effects are direct or transcript-mediated unresolved","Cross-talk between TARBP2's miRNA and direct-binding functions unquantified"]},{"year":2022,"claim":"Reported TARBP2 acting as a general lncRNA-binding partner (SNHG7, LINC01526) to alter transcript fate in BBB permeability and gastric cancer.","evidence":"RIP, RNA pull-down, half-life and luciferase assays, xenograft models","pmids":["35562351","36230863"],"confidence":"Low","gaps":["Binding domains/structural determinants not mapped","Single-lab observations without reciprocal validation","Generality of lncRNA recognition unclear"]},{"year":null,"claim":"How TARBP2 is partitioned among its DICER1-cofactor, direct mRNA-destabilizing, nuclear m6A/exosome, cell-cycle, and antiviral functions, and what governs target selection in each compartment, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of subcellular trafficking","Determinants distinguishing miRNA-dependent vs -independent targets unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,5,10,0]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,4,6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,10,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,3,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,10,11]}],"complexes":["RISC-loading complex (RLC)"],"partners":["DICER1","AGO2","TPR","MAVS","TRAF6","IRF7","NF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15633","full_name":"RISC-loading complex subunit TARBP2","aliases":["TAR RNA-binding protein 2","Trans-activation-responsive RNA-binding protein"],"length_aa":366,"mass_kda":39.0,"function":"Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. May also play a role in the production of short interfering RNAs (siRNAs) from double-stranded RNA (dsRNA) by DICER1 (By similarity) (PubMed:15973356, PubMed:16142218, PubMed:16271387, PubMed:16357216, PubMed:16424907, PubMed:17452327, PubMed:18178619). Binds in vitro to the PRM1 3'-UTR (By similarity). Seems to act as a repressor of translation (By similarity). For some pre-miRNA substrates, may also alter the choice of cleavage site by DICER1 (PubMed:23063653). Negatively regulates IRF7-mediated IFN-beta signaling triggered by viral infection by inhibiting the phosphorylation of IRF7 and promoting its 'Lys'-48-linked ubiquitination and degradation (PubMed:30927622) (Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1, and stimulates translation of TAR-containing RNAs (PubMed:11438532, PubMed:12475984, PubMed:2011739). This is achieved in part at least by binding to and inhibiting EIF2AK2/PKR, thereby reducing phosphorylation and inhibition of EIF2S1/eIF-2-alpha (PubMed:11438532). May also promote translation of TAR-containing RNAs independently of EIF2AK2/PKR (PubMed:12475984). Mediates recruitment of FTSJ3 methyltransferase to HIV-1 RNA, leading to 2'-O-methylation of the viral genome, allowing HIV-1 to escape the innate immune system (PubMed:30626973)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15633/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TARBP2","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2},{"gene":"MYO9B","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2},{"gene":"TPT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TARBP2","total_profiled":1310},"omim":[{"mim_id":"620127","title":"MICRO RNA 151A; MIR151A","url":"https://www.omim.org/entry/620127"},{"mim_id":"618411","title":"FTSJ RNA 2-PRIME-O-METHYLTRANSFERASE 3; FTSJ3","url":"https://www.omim.org/entry/618411"},{"mim_id":"612409","title":"RNA-BINDING MOTIF PROTEIN 14; RBM14","url":"https://www.omim.org/entry/612409"},{"mim_id":"612178","title":"HEN METHYLTRANSFERASE 1; HENMT1","url":"https://www.omim.org/entry/612178"},{"mim_id":"606241","title":"DICER 1, RIBONUCLEASE III; DICER1","url":"https://www.omim.org/entry/606241"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TARBP2"},"hgnc":{"alias_symbol":["Trbp"],"prev_symbol":[]},"alphafold":{"accession":"Q15633","domains":[{"cath_id":"3.30.160.20","chopping":"18-96","consensus_level":"high","plddt":90.9539,"start":18,"end":96},{"cath_id":"3.30.160.20","chopping":"159-225","consensus_level":"high","plddt":92.7558,"start":159,"end":225},{"cath_id":"3.30.160.20","chopping":"264-362","consensus_level":"high","plddt":88.942,"start":264,"end":362}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15633","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15633-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15633-F1-predicted_aligned_error_v6.png","plddt_mean":74.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TARBP2","jax_strain_url":"https://www.jax.org/strain/search?query=TARBP2"},"sequence":{"accession":"Q15633","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15633.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15633/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15633"}},"corpus_meta":[{"pmid":"19219043","id":"PMC_19219043","title":"A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function.","date":"2009","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19219043","citation_count":286,"is_preprint":false},{"pmid":"25437560","id":"PMC_25437560","title":"Deletion of human tarbp2 reveals cellular microRNA targets and cell-cycle function of TRBP.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25437560","citation_count":96,"is_preprint":false},{"pmid":"25043050","id":"PMC_25043050","title":"Metastasis-suppressor transcript destabilization through TARBP2 binding of mRNA hairpins.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25043050","citation_count":76,"is_preprint":false},{"pmid":"31300274","id":"PMC_31300274","title":"Nuclear TARBP2 Drives Oncogenic Dysregulation of RNA Splicing and Decay.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31300274","citation_count":68,"is_preprint":false},{"pmid":"23671264","id":"PMC_23671264","title":"Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma.","date":"2013","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23671264","citation_count":53,"is_preprint":false},{"pmid":"26582366","id":"PMC_26582366","title":"SUMOylation of TARBP2 regulates miRNA/siRNA efficiency.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26582366","citation_count":40,"is_preprint":false},{"pmid":"11641396","id":"PMC_11641396","title":"Organization of the human tarbp2 gene reveals two promoters that are repressed in an astrocytic cell line.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11641396","citation_count":30,"is_preprint":false},{"pmid":"30657254","id":"PMC_30657254","title":"TARBP2-mediated destabilization of Nanog overcomes sorafenib resistance in hepatocellular carcinoma.","date":"2019","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30657254","citation_count":28,"is_preprint":false},{"pmid":"30390472","id":"PMC_30390472","title":"TARBP2 negatively regulates IFN-β production and innate antiviral response by targeting MAVS.","date":"2018","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30390472","citation_count":22,"is_preprint":false},{"pmid":"30927622","id":"PMC_30927622","title":"TARBP2 inhibits IRF7 activation by suppressing TRAF6-mediated K63-linked ubiquitination of IRF7.","date":"2019","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30927622","citation_count":21,"is_preprint":false},{"pmid":"32305960","id":"PMC_32305960","title":"Hypoxia-induced let-7f-5p/TARBP2 feedback loop regulates osteosarcoma cell proliferation and invasion by inhibiting the Wnt signaling pathway.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32305960","citation_count":20,"is_preprint":false},{"pmid":"26486325","id":"PMC_26486325","title":"The role of TARBP2 in the development and progression of cancers.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26486325","citation_count":19,"is_preprint":false},{"pmid":"31891797","id":"PMC_31891797","title":"Actinidia Chinensis Planch Root extract attenuates proliferation and metastasis of hepatocellular carcinoma by inhibiting the DLX2/TARBP2/JNK/AKT pathway.","date":"2019","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31891797","citation_count":19,"is_preprint":false},{"pmid":"35562351","id":"PMC_35562351","title":"TARBP2-stablized SNHG7 regulates blood-brain barrier permeability by acting as a competing endogenous RNA to miR-17-5p/NFATC3 in Aβ-microenvironment.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35562351","citation_count":18,"is_preprint":false},{"pmid":"34249676","id":"PMC_34249676","title":"Loss of TARBP2 Drives the Progression of Hepatocellular Carcinoma via miR-145-SERPINE1 Axis.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34249676","citation_count":18,"is_preprint":false},{"pmid":"23690119","id":"PMC_23690119","title":"Microsatellite instability and TARBP2 mutation study in upper urinary tract urothelial carcinoma.","date":"2013","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23690119","citation_count":18,"is_preprint":false},{"pmid":"33484209","id":"PMC_33484209","title":"TARBP2 promotes tumor angiogenesis and metastasis by destabilizing antiangiogenic factor mRNAs.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33484209","citation_count":16,"is_preprint":false},{"pmid":"35008634","id":"PMC_35008634","title":"TARBP2 Suppresses Ubiquitin-Proteasomal Degradation of HIF-1α in Breast Cancer.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35008634","citation_count":10,"is_preprint":false},{"pmid":"27599909","id":"PMC_27599909","title":"shRNA‑mediated silencing of TARBP2 inhibits NCI‑H1299 non‑small cell lung cancer cell invasion and migration via the JNK/STAT3/AKT pathway.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27599909","citation_count":10,"is_preprint":false},{"pmid":"27980417","id":"PMC_27980417","title":"Clinicopathological Significance of TARBP2, APP, and ZNF395 in Breast Cancer.","date":"2016","source":"Breast cancer : basic and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/27980417","citation_count":10,"is_preprint":false},{"pmid":"36230863","id":"PMC_36230863","title":"LINC01526 Promotes Proliferation and Metastasis of Gastric Cancer by Interacting with TARBP2 to Induce GNG7 mRNA Decay.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36230863","citation_count":8,"is_preprint":false},{"pmid":"30759864","id":"PMC_30759864","title":"TARBP2-Enhanced Resistance during Tamoxifen Treatment in Breast Cancer.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30759864","citation_count":7,"is_preprint":false},{"pmid":"35452690","id":"PMC_35452690","title":"Grass carp (Ctenopharyngodon idella) Trans-Activation-Responsive RNA-binding protein 2 (TARBP2) inhibits apoptosis by decreasing PKR phosphorylation.","date":"2022","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35452690","citation_count":3,"is_preprint":false},{"pmid":"39278379","id":"PMC_39278379","title":"A molecular mechanism underlies grass carp (Ctenopharyngodon idella) TARBP2 regulating PKR-mediated cell apoptosis.","date":"2024","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39278379","citation_count":0,"is_preprint":false},{"pmid":"40992563","id":"PMC_40992563","title":"Spotted knifejaw (Oplegnathus punctatus) TARBP2 negatively regulates type I IFN responses to promote RGNNV replication.","date":"2025","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40992563","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.06.668327","title":"Robust CRISPR Screens Identify TPL1 as a Novel Long Noncoding RNA Driving Triple-Negative Breast Cancer Hallmarks","date":"2025-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.06.668327","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14825,"output_tokens":3821,"usd":0.050895,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11559,"output_tokens":4216,"usd":0.081598,"stage2_stop_reason":"end_turn"},"total_usd":0.132493,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"TARBP2 frameshift mutations in microsatellite-instable carcinomas cause diminished TRBP protein expression, defective miRNA processing, and destabilization of DICER1 protein; reintroduction of TRBP restores miRNA production and inhibits tumor growth.\",\n      \"method\": \"Mutational analysis, western blot, miRNA processing assays, rescue experiments in cancer cell lines\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutational sequencing, protein expression, functional miRNA processing assay, rescue experiment) replicated across tumor types\",\n      \"pmids\": [\"19219043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TARBP2 knockout alters Dicer processing sites in a subset of miRNAs but does not affect Dicer stability, overall miRNA abundance, or Argonaute loading; TRBP and PACT do not functionally compensate for one another, and only TRBP contributes to Dicer processing accuracy.\",\n      \"method\": \"CRISPR/Cas9 knockout of TARBP2 and PACT in human cells, small RNA sequencing, western blot for Dicer and Ago2\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple orthogonal readouts (sequencing, protein stability assays), single lab but rigorous controls including double-KO\",\n      \"pmids\": [\"25437560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TARBP2 is hyperphosphorylated by JNK during M phase when PKR is activated by cellular dsRNAs; hyperphosphorylation potentiates TARBP2's inhibitory activity on PKR, suppressing PKR during M-G1 transition.\",\n      \"method\": \"TARBP2 knockout cells, JNK inhibitor treatment, phosphorylation assays, PKR activity measurements across cell cycle phases\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacological inhibition and biochemical kinase assays, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"25437560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TARBP2 binds GC-rich structural cis-regulatory elements (TBSEs/sRSEs) in metastasis-suppressor mRNAs (APP and ZNF395) via its dsRNA-binding activity, destabilizing those transcripts to promote breast cancer invasion and metastasis.\",\n      \"method\": \"Whole-genome transcript stability measurements, RNA pull-down/biochemical binding assays, computational structure prediction, loss-of-function and rescue experiments in breast cancer cell lines, in vivo colonization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transcript stability profiling, biochemical binding, in vivo models), single lab but comprehensive mechanistic follow-up\",\n      \"pmids\": [\"25043050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TARBP2 is SUMOylated at K52; SUMOylation is enhanced by phosphorylation, stabilizes TARBP2 by repressing K48-linked ubiquitination, recruits Ago2 to form the RISC-loading complex (RLC), promotes pre-miRNA loading into the RLC, and stabilizes Ago2, thereby enhancing miRNA/siRNA efficiency.\",\n      \"method\": \"Site-directed mutagenesis (K52R), in vivo SUMOylation assays, Co-IP for Ago2 and Dicer, ubiquitination assays, RNAi reporter assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — active-site mutagenesis plus Co-IP and functional reporter assays, multiple orthogonal methods in single study\",\n      \"pmids\": [\"26582366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear TARBP2 binds pre-mRNAs and recruits m6A RNA methylation machinery, leading to deposition of m6A marks that inhibit efficient splicing and cause intron retention; TARBP2 then interacts with the nucleoprotein TPR to promote degradation of bound transcripts by the nuclear exosome, destabilizing target mRNAs including ABCA3 and FOXN3.\",\n      \"method\": \"RNA-protein binding assays, m6A methylation assays, Co-IP with TPR, nuclear fractionation, RNA-seq for intron retention, xenograft mouse models, TARBP2 overexpression/knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods (m6A assay, Co-IP, RNA-seq) plus in vivo validation, single lab but comprehensive mechanistic study\",\n      \"pmids\": [\"31300274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TARBP2 interacts with MAVS and disrupts MAVS-RIG-I and MAVS-TRAF3 associations, thereby negatively regulating virus-induced IFN-β production and innate antiviral response.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in 293T cells, IFN-β reporter assays, viral infection assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional reporter assays in single lab, moderate mechanistic follow-up\",\n      \"pmids\": [\"30390472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TARBP2 inhibits IRF7-mediated IFN-β production by impairing TRAF6-mediated K63-linked ubiquitination of IRF7 (a prerequisite for IRF7 phosphorylation); TARBP2 also destabilizes endogenous TRAF6 and participates in the IRF7-TRAF6 interaction.\",\n      \"method\": \"Co-IP, ubiquitination assays, phosphorylation assays, overexpression in 293T cells, Sendai virus infection\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assays in single lab, two orthogonal biochemical methods\",\n      \"pmids\": [\"30927622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TARBP2 protein is destabilized through autophagic-lysosomal proteolysis in sorafenib-resistant HCC cells; this TARBP2 loss stabilizes Nanog protein (a CSC marker), facilitating sorafenib resistance in a miRNA-independent manner.\",\n      \"method\": \"Lysosomal inhibitor treatment, protein stability assays, western blot, knockdown/overexpression in HCC cell lines\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitor plus protein stability assay, single lab, two orthogonal approaches\",\n      \"pmids\": [\"30657254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tamoxifen post-transcriptionally stabilizes TARBP2 protein through downregulation of Merlin, a TARBP2-interacting protein that enhances its proteasomal degradation; stabilized TARBP2 further stabilizes SOX2 protein, inducing tamoxifen resistance in ER+ breast cancer cells.\",\n      \"method\": \"Co-IP for Merlin-TARBP2 interaction, proteasomal inhibitor treatment, overexpression and knockdown in breast cancer cell lines, protein stability assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"30759864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TARBP2 physically interacts with the stem-loop structures in the 3'UTRs of antiangiogenic factor mRNAs (THBS1/2, TIMP1, SERPINF1) via its dsRNA-binding domains 1/2, leading to mRNA destabilization and promotion of tumor angiogenesis.\",\n      \"method\": \"RNA immunoprecipitation, 3'UTR reporter assays, mRNA stability assays, TARBP2 domain deletion analysis, in vitro and in vivo angiogenesis assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain-deletion binding assay combined with functional mRNA stability and reporter assays, single lab\",\n      \"pmids\": [\"33484209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TARBP2 suppresses proteasomal degradation of HIF-1α in breast cancer by downregulating multiple HIF-1α-targeting E3 ligases (VHL, FBXW7, TRAF6) and reducing HIF-1α ubiquitination, thereby maintaining HIF-1α protein stability under normoxia and hypoxia.\",\n      \"method\": \"Proteasome inhibitor treatment, ubiquitination assays, western blot for E3 ligases, TARBP2 overexpression/knockdown in breast cancer cells, IHC\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ubiquitination assay plus pharmacological and genetic perturbation, single lab\",\n      \"pmids\": [\"35008634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of TARBP2 reduces processing of miR-145, leading to upregulation of its target SERPINE1 (PAI-1), which promotes HCC cell proliferation, migration, and invasion; overexpression of miR-145 rescues the TARBP2-loss phenotype.\",\n      \"method\": \"shRNA knockdown, RNA-seq, luciferase reporter assay for miR-145/SERPINE1 interaction, rescue experiments in HCC cell lines\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay plus rescue epistasis experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"34249676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TARBP2 binds SNHG7 lncRNA as an RNA-binding protein, increasing SNHG7 half-life (transcript stabilization); this TARBP2-SNHG7 interaction leads to sequestration of miR-17-5p, derepression of NFATC3, and increased blood-brain barrier permeability in an Aβ microenvironment.\",\n      \"method\": \"RNA immunoprecipitation, mRNA half-life assay, overexpression/knockdown in endothelial cells, luciferase reporter assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and stability assay without rigorous mechanistic dissection of TARBP2 binding domain\",\n      \"pmids\": [\"35562351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TARBP2 interacts with LINC01526 lncRNA and is recruited by LINC01526 to degrade GNG7 mRNA, promoting gastric cancer proliferation and migration.\",\n      \"method\": \"RNA pull-down, Co-IP, mRNA stability assay, rescue experiments in gastric cancer cells, xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pulldown plus functional assay without mechanistic domain mapping\",\n      \"pmids\": [\"36230863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The TARBP2 gene has two adjacent promoters driving alternative first exons for TRBP1 and TRBP2 isoforms; TRBP2 transcription and translation start sites are located within the first intron of TRBP1; promoter activity is specifically repressed in human astrocytic cells compared to HeLa cells.\",\n      \"method\": \"Gene isolation and sequencing, promoter deletion analysis, reporter assays, 5' RACE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion analysis with reporter assays across multiple cell lines, single lab\",\n      \"pmids\": [\"11641396\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TARBP2 (TRBP) is a multifunctional dsRNA-binding protein that acts as a DICER1 cofactor to fine-tune miRNA processing site selection and stabilize DICER1 protein; it is SUMOylated (at K52) to facilitate RISC-loading complex assembly with Ago2; it undergoes JNK-mediated hyperphosphorylation in M phase to inhibit PKR and permit M-G1 transition; in the nucleus it recruits m6A methylation machinery and the nucleoprotein TPR to promote intron retention and exosome-mediated degradation of target pre-mRNAs; in the cytoplasm it directly binds structural elements (TBSEs) in the 3'UTRs of metastasis-suppressor and antiangiogenic mRNAs to destabilize them; and it negatively regulates innate antiviral signaling by disrupting MAVS-RIG-I/TRAF3 complexes and suppressing TRAF6-mediated K63-ubiquitination of IRF7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TARBP2 (TRBP) is a multifunctional double-stranded RNA-binding protein that operates in both miRNA biogenesis and direct sequence-specific control of mRNA stability across cancer, cell cycle, and innate immune contexts [#0, #3]. As a DICER1 cofactor, TARBP2 stabilizes DICER1 protein and is required for accurate Dicer cleavage-site selection on a subset of pre-miRNAs; loss-of-function frameshift mutations in microsatellite-instable carcinomas diminish TRBP, destabilize DICER1, and impair miRNA processing, while genetic knockout shifts Dicer processing sites without abolishing global miRNA abundance or Argonaute loading, an activity not shared with its paralog PACT [#0, #1]. SUMOylation at K52 stabilizes TARBP2 by repressing K48-linked ubiquitination and recruits Ago2 to assemble the RISC-loading complex, thereby enhancing small-RNA silencing efficiency [#4]. Independent of miRNAs, cytoplasmic TARBP2 binds GC-rich structural elements (TBSEs) in the 3'UTRs of metastasis-suppressor (APP, ZNF395) and antiangiogenic (THBS1/2, TIMP1, SERPINF1) transcripts via its dsRNA-binding domains to destabilize them, promoting invasion, metastasis, and tumor angiogenesis [#3, #10]. In the nucleus, TARBP2 binds pre-mRNAs, recruits the m6A methylation machinery to drive intron retention, and engages the nucleoprotein TPR to target the modified transcripts for nuclear exosome degradation [#5]. During M phase TARBP2 is hyperphosphorylated by JNK, potentiating its inhibition of PKR to permit the M-G1 transition [#2], and it negatively regulates antiviral signaling by disrupting MAVS-RIG-I/TRAF3 complexes and impairing TRAF6-mediated K63-ubiquitination of IRF7 [#6, #7]. TARBP2 protein levels are themselves tightly controlled by proteasomal and autophagic-lysosomal turnover, with the interactor Merlin promoting its degradation [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the genomic architecture of the TARBP2 locus, showing two adjacent promoters generate TRBP1/TRBP2 isoforms with cell-type-specific promoter regulation.\",\n      \"evidence\": \"Gene isolation, promoter deletion/reporter assays and 5' RACE across HeLa and astrocytic cells\",\n      \"pmids\": [\"11641396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of isoform choice not defined\", \"Mechanism of astrocyte-specific repression unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked TARBP2 to tumor suppression by showing its frameshift mutation impairs DICER1 stability and miRNA processing, addressing how miRNA biogenesis fails in microsatellite-instable cancers.\",\n      \"evidence\": \"Mutational analysis, western blot, miRNA processing and rescue assays in cancer cell lines\",\n      \"pmids\": [\"19219043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which specific miRNAs drive the tumor phenotype\", \"Mechanism of DICER1 stabilization by TRBP not detailed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Refined the DICER1 cofactor role by demonstrating TARBP2 governs Dicer processing-site accuracy rather than Dicer stability or global miRNA output, and is non-redundant with PACT.\",\n      \"evidence\": \"CRISPR/Cas9 single and double knockout, small RNA sequencing, western blot in human cells\",\n      \"pmids\": [\"25437560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent discrepancy with 2009 DICER1 stability finding not reconciled\", \"Determinants of which miRNAs require TRBP for accuracy unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a cell-cycle role: JNK hyperphosphorylates TARBP2 in M phase to potentiate PKR inhibition, answering how PKR is restrained during M-G1 transition.\",\n      \"evidence\": \"Knockout cells, JNK inhibitor, phosphorylation and PKR activity assays across cell cycle\",\n      \"pmids\": [\"25437560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites mediating PKR inhibition not mapped\", \"Identity of the M-phase dsRNAs activating PKR unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a miRNA-independent function in which TARBP2 directly binds structural 3'UTR elements to destabilize metastasis-suppressor mRNAs, explaining a pro-metastatic role.\",\n      \"evidence\": \"Transcript stability profiling, RNA binding assays, structure prediction, in vivo colonization assays in breast cancer cells\",\n      \"pmids\": [\"25043050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Decay machinery recruited by cytoplasmic TARBP2 not identified\", \"Full target repertoire beyond APP/ZNF395 incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SUMOylation at K52 as a regulatory switch that stabilizes TARBP2 and recruits Ago2 for RISC-loading complex assembly, connecting post-translational modification to silencing efficiency.\",\n      \"evidence\": \"K52R mutagenesis, in vivo SUMOylation, Co-IP, ubiquitination and RNAi reporter assays\",\n      \"pmids\": [\"26582366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO ligase responsible not identified\", \"Quantitative contribution of SUMOylation to physiological silencing unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended TARBP2 to innate immunity by showing it disrupts MAVS-RIG-I/TRAF3 complexes to dampen IFN-\\u03b2 production.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown in 293T, IFN-\\u03b2 reporter and viral infection assays\",\n      \"pmids\": [\"30390472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single overexpression system without endogenous validation\", \"Direct binding interface with MAVS not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a nuclear pathway in which TARBP2 recruits m6A machinery and TPR to drive intron retention and exosome-mediated decay of pre-mRNAs, establishing a chromatin-proximal mode of gene control.\",\n      \"evidence\": \"RNA-protein binding, m6A assays, Co-IP with TPR, intron-retention RNA-seq, xenograft models\",\n      \"pmids\": [\"31300274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which m6A writer subunit TARBP2 contacts not specified\", \"Signals partitioning TARBP2 between nucleus and cytoplasm unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed TARBP2 inhibits IRF7-driven IFN-\\u03b2 by impairing TRAF6-mediated K63-ubiquitination of IRF7 and destabilizing TRAF6, broadening its antiviral suppressor role.\",\n      \"evidence\": \"Co-IP, ubiquitination and phosphorylation assays, Sendai virus infection in 293T\",\n      \"pmids\": [\"30927622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous physiological context limited to overexpression system\", \"Relationship to the MAVS-disruption mechanism not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated TARBP2 protein abundance is set by competing turnover routes (autophagic-lysosomal and Merlin-promoted proteasomal degradation), with miRNA-independent downstream effects on Nanog and SOX2 in drug resistance.\",\n      \"evidence\": \"Lysosomal/proteasomal inhibitors, Co-IP for Merlin, protein stability assays in HCC and breast cancer lines\",\n      \"pmids\": [\"30657254\", \"30759864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TARBP2 stabilizes Nanog/SOX2 not defined\", \"In vivo relevance of these turnover routes not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the cytoplasmic mRNA-destabilization role to antiangiogenic transcripts and miR-145 processing, and revealed TARBP2 control of HIF-1\\u03b1 stability via E3 ligase downregulation.\",\n      \"evidence\": \"RIP, 3'UTR reporter and stability assays, domain deletion, miR-145 rescue, ubiquitination assays in cancer cells and xenografts\",\n      \"pmids\": [\"33484209\", \"34249676\", \"35008634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HIF-1\\u03b1 and angiogenesis effects are direct or transcript-mediated unresolved\", \"Cross-talk between TARBP2's miRNA and direct-binding functions unquantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported TARBP2 acting as a general lncRNA-binding partner (SNHG7, LINC01526) to alter transcript fate in BBB permeability and gastric cancer.\",\n      \"evidence\": \"RIP, RNA pull-down, half-life and luciferase assays, xenograft models\",\n      \"pmids\": [\"35562351\", \"36230863\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding domains/structural determinants not mapped\", \"Single-lab observations without reciprocal validation\", \"Generality of lncRNA recognition unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TARBP2 is partitioned among its DICER1-cofactor, direct mRNA-destabilizing, nuclear m6A/exosome, cell-cycle, and antiviral functions, and what governs target selection in each compartment, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of subcellular trafficking\", \"Determinants distinguishing miRNA-dependent vs -independent targets unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 5, 10, 0]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 10, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 10, 11]}\n    ],\n    \"complexes\": [\"RISC-loading complex (RLC)\"],\n    \"partners\": [\"DICER1\", \"AGO2\", \"TPR\", \"MAVS\", \"TRAF6\", \"IRF7\", \"NF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}