{"gene":"TAF15","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1996,"finding":"TAF15 (hTAFII68) was identified as a novel TBP-associated factor that co-purifies with a subpopulation of TFIID complexes and also co-purifies with RNA polymerase II, entering the preinitiation complex together with Pol II. The protein contains a consensus RNA-binding domain (RNP-CS) and binds both RNA and single-stranded DNA.","method":"Biochemical co-purification, RNA/ssDNA binding assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution and co-purification with multiple orthogonal approaches; foundational paper independently replicated by subsequent work","pmids":["8890175"],"is_preprint":false},{"year":1998,"finding":"TAF15 (hTAFII68) interacts with specific TFIID subunits and specific subunits of RNA polymerase II. In vitro binding studies showed EWS and TAF15 interact with the same TFIID subunits, suggesting their presence in the same TFIID complex is mutually exclusive.","method":"In vitro binding assays, co-immunoprecipitation from nuclear extracts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays with defined subunits plus co-purification; replicated and extended findings from the 1996 EMBO paper","pmids":["9488465"],"is_preprint":false},{"year":2008,"finding":"TAF15 is present in both the nucleus and cytoplasm of most cell types. FET proteins (including TAF15) are targeted to stress granules induced by heat shock and oxidative stress. TAF15 (and FUS) were also detected in spreading initiation centers of adhering cells.","method":"Immunofluorescence, subcellular fractionation, live-cell imaging in multiple human cell types","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments across multiple cell types with functional context (stress response, cell spreading); single study","pmids":["18620564"],"is_preprint":false},{"year":2008,"finding":"Endogenous TAF15 is methylated in vivo at its RGG repeats by PRMT1. PRMT1 was identified as a TAF15-interacting protein and the major PRMT responsible for this methylation. Methylation of the RGG-containing C-terminus affects TAF15 subcellular localization (nucleus-cytoplasm shuttling) and is required for TAF15 to positively regulate expression of its target genes.","method":"Co-immunoprecipitation, in vitro methylation assay, subcellular fractionation, gene expression analysis after PRMT1 inhibition/knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation assay plus Co-IP plus functional readout (target gene regulation), multiple orthogonal methods in one study","pmids":["19124016"],"is_preprint":false},{"year":2009,"finding":"A fraction of TAF15 specifically associates with human U1 snRNA to form a novel U1-TAF15 snRNP that is distinct from the canonical spliceosomal U1-Sm snRNP (none of the known Sm or U1-specific proteins co-precipitate). The U1-TAF15 snRNP tightly associates with chromatin in an RNA-dependent manner and accumulates in nucleolar caps upon transcriptional inhibition. The Sm-binding motif of U1 snRNA is essential for biogenesis of both U1-Sm and U1-TAF15 snRNPs.","method":"RNA immunoprecipitation, chromatin fractionation, transcription inhibition experiments, mutational analysis of U1 snRNA","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods (co-IP, chromatin fractionation, mutagenesis) establishing a novel RNP complex in one rigorous study","pmids":["19282884"],"is_preprint":false},{"year":2011,"finding":"In FTLD-FUS (but not ALS-FUS-mutation cases), all endogenous FET proteins including TAF15 and EWS shift to insoluble fractions. Cell culture experiments showed that inhibition of Transportin-mediated nuclear import recruits all endogenous FET proteins (including TAF15) into cytoplasmic stress granules, mimicking the FTLD finding.","method":"Immunoblot of post-mortem tissue fractions, cell culture experiments with Transportin inhibition, immunohistochemistry","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation of human tissue plus cell culture mechanistic experiment with defined inhibitor; single lab","pmids":["21856723"],"is_preprint":false},{"year":2011,"finding":"A fraction of nuclear TAF15 associates with the spliceosomal U1 snRNP complex, as demonstrated by co-precipitation of U1 snRNA, U1-70K, and Sm proteins. Pull-down assays showed a direct protein-protein interaction between TAF15 and U1C that required the N-terminal domain of TAF15. In vivo UV cross-linking showed TAF15 directly contacts RNA (likely Pol II transcripts).","method":"Immunoprecipitation from HeLa nuclear extracts, pull-down with recombinant proteins, UV cross-linking","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus recombinant protein pull-down plus in vivo UV crosslinking; single lab","pmids":["22019700"],"is_preprint":false},{"year":2012,"finding":"TAF15 knockdown affects expression of genes involved in cell cycle and apoptosis, causes growth inhibition and increased apoptosis. TAF15 regulates cell cycle genes post-transcriptionally through a pathway involving miRNAs from the onco-miR-17 locus (miR-17-5p and miR-20a), which in turn control CDKN1A/p21 levels. TAF15 depletion decreases levels of miR-17-5p and miR-20a.","method":"siRNA knockdown, global gene expression profiling, miRNA quantification, cell proliferation/apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined phenotypic readout plus miRNA profiling; single lab, multiple methods","pmids":["23128393"],"is_preprint":false},{"year":2012,"finding":"The C-terminal RGG domain of TAF15 is responsible for shuttling between the nucleus and cytoplasm. A transportin-dependent nuclear localization signal (NLS) resides at the C-terminus. TAF15 localization was shown to depend on ongoing transcription, and independent domains engage in nucleolar capping upon transcription inhibition. TAF15 localization is differentially regulated in HeLa versus neuronal HT22 cells.","method":"Domain deletion constructs, GFP fusions, transportin inhibition assays, transcription inhibition experiments, subcellular fractionation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping with multiple constructs plus pharmacological perturbations; single lab","pmids":["22771914"],"is_preprint":false},{"year":2013,"finding":"TAF15 binds to conserved RNA targets in human brain and mouse neurons enriched in transcripts encoding synaptic proteins. TAF15 is required for a critical alternative splicing event of the Grin1 (NMDA receptor NR1 subunit) that controls NR1 activity and trafficking. Unlike FUS and TDP-43, TAF15 has a minimal role in general alternative splicing.","method":"HITS-CLIP, RNA-seq, siRNA knockdown in neurons, splicing analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — HITS-CLIP plus RNA-seq plus KD with specific splicing readout; multiple orthogonal methods in one study","pmids":["23416048"],"is_preprint":false},{"year":2013,"finding":"FUS, EWSR1, and TAF15 form homo- and heterocomplexes via a conserved N-terminal motif (FETBM1). This interaction is RNA- and DNA-independent and robust up to 1M NaCl. The FETBM1 motif is also required for binding of normal full-length FET proteins to their oncogenic fusion proteins.","method":"Recombinant protein pulldown, mass spectrometry, mutagenesis of FETBM1 motif","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — recombinant protein reconstitution plus mutagenesis plus MS; multiple orthogonal methods in one study","pmids":["23975937"],"is_preprint":false},{"year":2014,"finding":"TAF15 selectively co-immunoprecipitates with the higher molecular weight hnRNP M3/4 isoforms (contrasting with FUS which prefers hnRNP M1/2). This association is mediated through direct protein-protein interactions via the amino-termini of the TET proteins, independently of RNA.","method":"Co-immunoprecipitation from HeLa nuclear extracts, recombinant protein pulldown, immunofluorescence co-localization","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RNA-independent direct pulldown; single lab","pmids":["24474660"],"is_preprint":false},{"year":2015,"finding":"The solution NMR structure of the TAF15 RRM domain was determined. RNA binding occurs through a non-canonical mode: rather than classical stacking interactions between nitrogen bases and aromatic amino acids at RNP sites, moderate-affinity hydrogen bonding between stem-loop RNA bases and a concave face on the RRM surface primarily mediates the interaction. RNA binding depends on structural elements in the RNA rather than sequence alone.","method":"Solution NMR spectroscopy, isothermal titration calorimetry, docking, molecular dynamics simulation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure determination plus calorimetric binding measurements plus MD simulation; multiple orthogonal methods","pmids":["26612539"],"is_preprint":false},{"year":2016,"finding":"TAF15 binds ~4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns and are enriched in 3' UTRs. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. Unlike FUS and TDP-43, TAF15 has minimal role in alternative splicing.","method":"CLIP-seq, RNA Bind-N-Seq, RNA-seq in motor neurons and neural progenitors, double KO analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent binding technologies (CLIP-seq + RBNS) plus loss-of-function RNA-seq; replicated across multiple cell types","pmids":["27378374"],"is_preprint":false},{"year":2017,"finding":"TAF15 low-complexity (LC) domain forms amyloid-like hydrogel fibrils that bind the CTD of RNA polymerase II. NMR and FRAP showed that heptad positions far from the acidic C-terminal tail of RNA pol II CTD bind TAF15 fibrils most avidly. Mutation of CTD lysines at heptad position 7 to consensus serines reduced TAF15 fibril binding, implicating electrostatic interactions in complex formation.","method":"NMR spectroscopy (spin relaxation, dark-state exchange saturation transfer), hydrogel fibril FRAP assay, site-directed mutagenesis of CTD lysines","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR plus functional fibril-binding assay plus mutagenesis; multiple orthogonal methods","pmids":["28945358"],"is_preprint":false},{"year":2017,"finding":"PRMT1 shows differential interaction with RGG-boxes of TAF15 compared to FUS and EWS. The Asp residue in TAF15's YGGDR(S/G)G repeats confers poor binding to PRMT1, resulting in reduced overall methylation of TAF15 compared to other FET proteins.","method":"Peptide-based polyRGG substrate assays, novel 2-hybrid binding assay","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — biochemical peptide binding assay and 2-hybrid; single lab, limited cellular validation","pmids":["29193371"],"is_preprint":false},{"year":2018,"finding":"TAF15 is phosphorylated on tyrosine residue(s) by v-Src kinase in vitro and in vivo. TAF15 associates with the SH3 domains of v-Src and other cell signaling proteins. Full-length v-Src stimulates TAF15-mediated transcriptional activation, while dominant-negative Src reduces it in a dose-dependent fashion.","method":"In vitro kinase assay, co-immunoprecipitation with SH3 domains, transcriptional reporter assays, dominant-negative overexpression","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus Co-IP plus transcriptional reporter; multiple methods, single lab","pmids":["15094065"],"is_preprint":false},{"year":2018,"finding":"In a Drosophila model, parkin directly binds to TAF15. Parkin overexpression suppresses TAF15-induced toxicity (defective lifespan and locomotion), and overexpression of parkin in neuronal cells reduces TAF15 protein levels through parkin's E3 ubiquitin ligase activity.","method":"Co-immunoprecipitation in Drosophila, genetic overexpression/loss-of-function, western blot quantification of TAF15 levels","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo genetic rescue plus protein level assay; Drosophila model, single lab","pmids":["30339961"],"is_preprint":false},{"year":2020,"finding":"GSK-3β (Shaggy) is abnormally activated in neurons of TAF15-expressing Drosophila. GSK-3β inhibition (pharmacological or genetic) reduces TAF15 protein levels and suppresses TAF15-induced neurotoxicity. The SCF-Slimb E3 ubiquitin ligase complex genetically interacts with TAF15 and is critical for GSK-3β-mediated suppression of TAF15 toxicity.","method":"Transgenic Drosophila model, pharmacological GSK-3β inhibition (lithium), genetic epistasis with F-box proteins, western blot, immunohistochemistry","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus pharmacological inhibition plus protein level assay in vivo; single lab, Drosophila model","pmids":["32915460"],"is_preprint":false},{"year":2021,"finding":"In Xenopus tropicalis, Taf15 regulates dorsoanterior neural development through two distinct mechanisms on a single target fgfr4: (1) maternal+zygotic Taf15 depletion causes intron retention in fgfr4, and (2) depletion of zygotic Taf15 alone reduces total fgfr4 transcript levels, indicating both post-transcriptional and transcriptional modes of regulation.","method":"Morpholino/CRISPR depletion in Xenopus, RNA-seq for exon usage and transcript abundance, epistasis with fgfr4 and ventx2.1","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in vivo with RNA-seq identifying two distinct mechanisms; single lab, Xenopus ortholog","pmids":["34345915"],"is_preprint":false},{"year":2022,"finding":"The C-terminal RGG domain of TAF15 associates with SRPK1, downregulates SRPK1 kinase activity, partially relocalizes SRPK1 to the nucleus, and results in hypophosphorylation of SR proteins, inhibition of pre-mRNA splicing of a reporter minigene, and inhibition of Lamin B receptor phosphorylation.","method":"Co-immunoprecipitation, kinase activity assay, reporter minigene splicing assay, western blot for SR protein phosphorylation, fluorescence microscopy","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus enzymatic activity assay plus functional splicing reporter; single lab, multiple methods","pmids":["36611919"],"is_preprint":false},{"year":2022,"finding":"TIF1γ binds TBP in competition with TAF15 and impedes TAF15/TBP-mediated IL-6 transactivation. TIF1γ modifies TAF15 through multi-mono-ubiquitylation and drives nuclear export of TAF15. TAF15/TBP complex activity is required for IL-6 activation-induced EMT and invasion of lung adenocarcinoma cells.","method":"Co-immunoprecipitation in human cell lines, ubiquitylation assay, nuclear/cytoplasmic fractionation, luciferase reporter for IL-6 transactivation, EMT/invasion assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitylation assay plus fractionation plus transcriptional reporter; single lab","pmids":["36261009"],"is_preprint":false},{"year":2022,"finding":"The SGYS motif within the TAF15 prion-like domain (PrLD) is a critical segment for amyloid fibril formation. ALS-associated mutation E71G in the T2 segment (Y56GQSQSGYSQSYGGYENQ73) significantly enhances aggregation. The T2 peptide with strong β-amyloid-forming tendency can induce liquid-to-solid phase transition of TAF15-PrLD protein. The SGYS motif maintains a stable β-sheet through intermolecular hydrogen bonds and π-π stacking.","method":"Thioflavin T aggregation assay, molecular dynamics simulation, mutagenesis, phase separation microscopy","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical aggregation assay plus MD simulation plus mutagenesis; multiple methods, single lab","pmids":["35643629"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of TAF15 amyloid filaments extracted from FTLD-FUS patient brains were determined. The filament fold is formed from residues 7–99 in the low-complexity domain (LCD) of TAF15, was identical among four individuals, and the same fold was found in motor cortex and brainstem of two individuals with upper/lower motor neuron pathology. This establishes TAF15 (not FUS) as the primary amyloid-forming protein in FTLD-FUS (now FTLD-TAF15).","method":"Cryo-electron microscopy of ex vivo amyloid filaments from post-mortem human brain","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of ex vivo material from four independent patients with identical fold; replicated across multiple brain regions","pmids":["38057661"],"is_preprint":false},{"year":2023,"finding":"TAF15 directly binds the promoter region of FASN to facilitate its transcription, promoting lipid steatosis. TAF15 also interacts with p65 (NF-κB subunit) and activates NF-κB signaling, increasing proinflammatory cytokine secretion and triggering M1 macrophage polarization. Both effects were shown in hepatocyte-specific AAV-knockdown and overexpression mouse models of NASH.","method":"CUT&Tag, dual-luciferase reporter assay, co-immunoprecipitation, immunofluorescence, hepatocyte-specific AAV knockdown/overexpression in mice","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-like CUT&Tag plus luciferase reporter plus Co-IP plus in vivo mouse model; single lab","pmids":["37183512"],"is_preprint":false},{"year":2023,"finding":"TAF15 in tumor-associated macrophages transcriptionally activates SOCS1, thereby inhibiting the JAK2/STAT1 signaling pathway and suppressing M1 macrophage polarization, promoting M2 polarization and ICC progression.","method":"CUT&Tag, dual-luciferase reporter assay, CRISPR-Cas9 TAF15 knockout in THP-1 cells, in vitro co-culture, in vivo M2pepLNP-siTAF15 treatment","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag plus luciferase plus CRISPR KO plus in vivo; single lab","pmids":["41244301"],"is_preprint":false},{"year":2024,"finding":"TAF15 is a nuclear substrate of PKA. PKA-mediated phosphorylation of TAF15 alters its binding to target transcripts related to mRNA maturation, splicing, and protein-binding functions, as shown by iCLIP experiments comparing phosphorylated vs. unphosphorylated TAF15.","method":"iCLIP (crosslinking immunoprecipitation), PKA substrate identification, cAMP pathway activation","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iCLIP with pathway perturbation; single lab, limited mechanistic follow-up","pmids":["38568213"],"is_preprint":false},{"year":2024,"finding":"CypA interacts with TAF15, stabilizes it by suppressing proteasomal degradation, and promotes its nuclear localization. TAF15 in turn positively regulates STAT5A. This forms a CypA/TAF15/STAT5A/miR-514a-3p feedback loop driving EMT in ovarian cancer.","method":"Co-immunoprecipitation, mass spectrometry, proteasome inhibition assay, subcellular fractionation, western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS plus functional rescue; single lab","pmids":["39402372"],"is_preprint":false},{"year":2025,"finding":"TAF15's C-terminal low-complexity (LC) domain undergoes phase separation and mediates dynamic interactions with hnRNPA0, which enhances TAF15's transcriptional activity. Domain-swapping with FUS showed the C-terminal LC domain is both necessary and sufficient for hnRNPA0 responsiveness. Phosphomimic mutations in the C-terminal LC domain disrupt hnRNPA0 interaction. ALS-linked mutations in TAF15 impair phase separation, reduce hnRNPA0 binding, and eliminate transcriptional enhancement.","method":"Domain-swap experiments, phosphomimic mutagenesis, ALS-linked point mutations, transcriptional reporter assays, phase separation microscopy","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutational analyses plus functional transcription assay plus phase separation microscopy; single lab","pmids":["41085196"],"is_preprint":false},{"year":2009,"finding":"TAF15 is specifically cleaved by caspases-3 and -7 at the consensus sequence 106DQPD/Y110. Site-directed mutagenesis confirmed this as the sole caspase-3/7 cleavage site. TAF15 was cleaved at more than one site in staurosporine-treated Jurkat cells, suggesting additional proteolytic regulation in apoptosis.","method":"In vitro caspase cleavage assay, site-directed mutagenesis, cell-based apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay plus site-directed mutagenesis; single lab","pmids":["19426707"],"is_preprint":false},{"year":2025,"finding":"TAF15 forms amyloid fibrils under physiological conditions that propagate in a prion-like fashion between cells. Patient-derived TAF15 aggregates from aFTLD-U brains seed aggregation and transmit serially between cells. Seeding is specific to TAF15 and does not cross-seed with FUS. Computational and peptide mapping identified multiple aggregation-prone regions in the TAF15 low-complexity domain that coincide with ex vivo filament core hotspots.","method":"Recombinant fibril formation, single-fluorophore biosensor for cellular propagation, patient brain extract seeding, peptide aggregation mapping, computational prediction","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — recombinant fibril assay plus patient material seeding plus cellular propagation assay; preprint, not yet peer reviewed","pmids":["bio_10.1101_2025.11.17.688886"],"is_preprint":true},{"year":2026,"finding":"Acute depletion of EWSR1 induces compensatory reorganization of both FUS and TAF15 to closely resemble EWSR1's organization with nascent RNA, demonstrating functional redundancy within the FET family for homeostatic regulation of nascent RNA levels. Nanoscale imaging showed TAF15 redistributes to enhance clustering with newly synthesized RNA upon EWSR1 loss.","method":"Acute EWSR1 depletion, nanoscale fluorescence imaging, nascent RNA labeling","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — imaging-based localization with functional inference; preprint, single lab","pmids":["42051291"],"is_preprint":true},{"year":2026,"finding":"All three proposed subtypes of FTLD-FET (aFTLD-U, NIFID, BIBD) are characterized by TAF15 amyloid filaments (not FUS filaments). Four distinct TAF15 filament folds were identified among NIFID cases and distinct folds for BIBD cases. A TAF15 Y38C variant was found in one BIBD case whose filament fold cannot incorporate wild-type TAF15 despite heterozygosity, suggesting this variant drives TAF15 filament assembly.","method":"Cryo-EM structure determination from post-mortem brain tissue of 17 individuals; genetic sequencing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures from 17 independent cases with genetic variant analysis; preprint, extends peer-reviewed 2023 Nature paper","pmids":["41648099"],"is_preprint":true}],"current_model":"TAF15 is a multifunctional FET-family RNA/ssDNA-binding protein that associates with subpopulations of TFIID and RNA polymerase II to participate in transcription initiation; its RGG-rich C-terminal low-complexity domain undergoes arginine methylation by PRMT1 (regulating subcellular localization and gene activation), tyrosine phosphorylation by Src, and serine phosphorylation by PKA (altering RNA-binding specificity), and forms amyloid-like assemblies that bind the RNA pol II CTD via electrostatic interactions with specific CTD lysines; the RRM domain recognizes RNA stem-loops through a non-canonical hydrogen-bonding mode; TAF15 forms homo- and hetero-complexes with FUS and EWSR1 via a conserved N-terminal FETBM1 motif, associates with a distinct U1-TAF15 snRNP and with spliceosomal U1C protein, regulates alternative splicing of neuronal targets (notably Grin1) and mRNA stability, controls cell proliferation through a miR-17 locus–CDKN1A axis, and in disease conditions assembles into structurally defined amyloid filaments (low-complexity domain residues 7–99) that propagate in a prion-like manner and constitute the primary pathological aggregates in FTLD-TAF15."},"narrative":{"mechanistic_narrative":"TAF15 is a multifunctional FET-family RNA/single-stranded-DNA-binding protein that couples transcription to RNA processing and, in disease, becomes the principal amyloid-forming species in frontotemporal lobar degeneration [PMID:8890175, PMID:38057661]. It was first isolated as a TBP-associated factor that co-purifies with a subpopulation of TFIID and enters the RNA polymerase II preinitiation complex, binding both RNA and ssDNA through a consensus RNA-binding domain [PMID:8890175, PMID:9488465]. Its RRM engages target RNAs through a non-canonical hydrogen-bonding mode that reads RNA stem-loop structure rather than sequence alone [PMID:26612539], and transcriptome-wide it binds thousands of structured, GGUA-enriched transcripts—enriched for synaptic mRNAs—where it controls RNA turnover and a specific Grin1 alternative-splicing event, while contributing minimally to global splicing [PMID:23416048, PMID:27378374]. TAF15 assembles into homo- and hetero-complexes with FUS and EWSR1 via a conserved, RNA-independent N-terminal FETBM1 motif [PMID:23975937], and a fraction associates with U1 snRNP through direct contact with U1C to form a distinct U1-TAF15 snRNP [PMID:19282884, PMID:22019700]. Its activity is governed by extensive post-translational modification of the RGG-rich C-terminal low-complexity domain: PRMT1-mediated arginine methylation regulating shuttling and target-gene activation [PMID:19124016], Src tyrosine phosphorylation enhancing transcriptional activation [PMID:15094065], and PKA serine phosphorylation that retunes RNA-binding specificity [PMID:38568213]. The same low-complexity domain phase-separates and forms amyloid-like fibrils that bind the RNA polymerase II CTD through electrostatic contacts with heptad-position lysines [PMID:28945358, PMID:41085196]. In FTLD, TAF15 low-complexity-domain residues 7–99 fold into structurally defined amyloid filaments that are identical across patients, establishing TAF15 rather than FUS as the primary pathological aggregate in FTLD-TAF15 [PMID:38057661]. TAF15 also functions as a sequence-specific promoter-binding transcriptional activator in cancer and metabolic contexts, driving FASN, SOCS1, and NF-κB-dependent programs [PMID:37183512, PMID:41244301].","teleology":[{"year":1996,"claim":"Establishing TAF15's biochemical identity answered whether it was a transcription factor, showing it is a TBP-associated factor bridging TFIID and Pol II that also binds nucleic acids.","evidence":"Biochemical co-purification with TFIID and Pol II plus RNA/ssDNA binding assays","pmids":["8890175"],"confidence":"High","gaps":["Did not define which promoters or genes depend on TAF15","RNA-binding specificity unresolved"]},{"year":1998,"claim":"Mapping TAF15 and EWS contacts within TFIID addressed how FET proteins partition among basal machinery, indicating mutually exclusive incorporation into TFIID.","evidence":"In vitro binding assays and Co-IP with defined TFIID and Pol II subunits","pmids":["9488465"],"confidence":"High","gaps":["Functional consequence of mutual exclusivity untested","Stoichiometry in vivo unknown"]},{"year":2008,"claim":"Localization and methylation studies addressed how TAF15 trafficking is controlled, identifying PRMT1 as the RGG arginine methyltransferase that governs nucleocytoplasmic shuttling and target-gene activation, and placing TAF15 in stress granules.","evidence":"Immunofluorescence/fractionation across cell types; Co-IP, in vitro methylation, gene expression after PRMT1 perturbation","pmids":["18620564","19124016"],"confidence":"Medium","gaps":["Specific methylated arginines not all mapped","Link between methylation and stress-granule recruitment unclear"]},{"year":2009,"claim":"Discovery of a U1-TAF15 snRNP and caspase cleavage addressed how TAF15 connects to splicing machinery and apoptotic regulation, defining a non-canonical chromatin-associated U1 particle and a caspase-3/7 cleavage site.","evidence":"RNA-IP, chromatin fractionation, U1 mutagenesis; in vitro caspase cleavage with site-directed mutagenesis","pmids":["19282884","19426707"],"confidence":"High","gaps":["Function of the U1-TAF15 snRNP not established","Biological role of caspase cleavage fragment unknown"]},{"year":2011,"claim":"FTLD fractionation and the U1C interaction addressed the disease relevance and spliceosomal coupling of TAF15, showing FET-protein insolubility in FTLD-FUS and a direct N-terminal TAF15–U1C contact.","evidence":"Post-mortem tissue immunoblot, Transportin-inhibition cell models; reciprocal Co-IP, recombinant pulldown, UV crosslinking","pmids":["21856723","22019700"],"confidence":"Medium","gaps":["Whether TAF15 or FUS is the primary aggregate not yet resolved in 2011","Direct RNA targets in vivo incompletely defined"]},{"year":2012,"claim":"Domain mapping and the miR-17/CDKN1A work addressed how TAF15 controls its own localization and cell proliferation, defining a C-terminal transportin-dependent NLS and a post-transcriptional growth-control axis.","evidence":"GFP-fusion domain deletions with transportin/transcription inhibition; siRNA knockdown with gene/miRNA profiling and proliferation assays","pmids":["22771914","23128393"],"confidence":"Medium","gaps":["Mechanism by which TAF15 controls miR-17 locus unknown","Cell-type-specific localization rules not generalized"]},{"year":2013,"claim":"CLIP-based target identification and FET heterocomplex mapping addressed what RNAs TAF15 regulates and how FET proteins assemble, defining synaptic-transcript binding, a specific Grin1 splicing role, and the RNA-independent FETBM1 interaction motif.","evidence":"HITS-CLIP, RNA-seq, neuronal knockdown; recombinant pulldown, mass spectrometry, FETBM1 mutagenesis","pmids":["23416048","23975937"],"confidence":"High","gaps":["Functional significance of most bound transcripts untested","Whether FET heterocomplexes act in transcription or RNA processing not separated"]},{"year":2014,"claim":"The hnRNP M isoform-selective interaction addressed how individual FET proteins acquire distinct partnerships, showing TAF15 preferentially binds hnRNP M3/4 via its amino-terminus.","evidence":"Co-IP, recombinant pulldown, immunofluorescence co-localization","pmids":["24474660"],"confidence":"Medium","gaps":["Functional outcome of the TAF15–hnRNP M complex unknown","Single lab without reciprocal in vivo validation"]},{"year":2015,"claim":"The RRM solution structure addressed the molecular basis of TAF15 RNA recognition, revealing a non-canonical hydrogen-bonding interface that reads RNA structure rather than sequence.","evidence":"Solution NMR, ITC, docking and molecular dynamics","pmids":["26612539"],"confidence":"High","gaps":["In vivo relevance of structure-based recognition not tested","Contribution of RGG domain to RNA affinity not modeled here"]},{"year":2016,"claim":"Genome-wide binding in brain addressed TAF15's transcriptome-scale function, confirming GGUA-motif binding, 3'UTR enrichment, RNA-turnover control shared with FUS, and minimal splicing role.","evidence":"CLIP-seq, RNA Bind-N-Seq, RNA-seq, double knockout","pmids":["27378374"],"confidence":"High","gaps":["Mechanism linking binding to turnover unresolved","Redundancy boundaries with FUS not fully mapped"]},{"year":2017,"claim":"LC-domain fibril and PRMT1-selectivity studies addressed how TAF15 engages the Pol II CTD and why it is hypomethylated, defining electrostatic CTD-lysine contacts and a methylation-limiting Asp in its RGG repeats.","evidence":"NMR, hydrogel fibril FRAP, CTD lysine mutagenesis; peptide polyRGG assays and 2-hybrid binding","pmids":["28945358","29193371"],"confidence":"High","gaps":["Whether CTD-fibril binding occurs at native concentrations in cells untested","Consequence of reduced methylation for TAF15 function not directly shown"]},{"year":2018,"claim":"Src phosphorylation and Drosophila parkin work addressed signaling control and turnover of TAF15, showing tyrosine phosphorylation enhances transcriptional activation and parkin ubiquitin-ligase activity lowers TAF15 levels and toxicity.","evidence":"In vitro kinase and SH3 Co-IP with reporter assays; Drosophila Co-IP, genetic rescue, protein-level westerns","pmids":["15094065","30339961"],"confidence":"Medium","gaps":["Phosphorylated residues and direct transcriptional mechanism not mapped","Parkin–TAF15 relationship not confirmed in mammalian neurons"]},{"year":2020,"claim":"GSK-3β/SCF-Slimb genetics addressed the degradation pathway controlling TAF15 toxicity, showing kinase activation and an E3 ligase complex modulate TAF15 levels and neurotoxicity.","evidence":"Transgenic Drosophila, lithium inhibition, F-box epistasis, westerns and immunohistochemistry","pmids":["32915460"],"confidence":"Medium","gaps":["Direct phosphorylation of TAF15 by GSK-3β not demonstrated","Mammalian relevance untested"]},{"year":2021,"claim":"Xenopus depletion addressed TAF15's developmental role, showing it regulates a single target (fgfr4) through both intron retention and transcript-abundance control during neural development.","evidence":"Morpholino/CRISPR depletion, RNA-seq exon/abundance analysis, epistasis","pmids":["34345915"],"confidence":"Medium","gaps":["Whether dual regulation generalizes beyond fgfr4 unknown","Ortholog-specific; mammalian developmental role untested"]},{"year":2022,"claim":"SRPK1, TIF1γ, and PrLD aggregation studies addressed how TAF15 modulates splicing kinases, how it is competitively regulated at TBP, and what drives its aggregation, defining SRPK1 inhibition, TIF1γ-mediated ubiquitylation/export, and an SGYS β-amyloid motif sensitized by ALS mutation E71G.","evidence":"Co-IP, kinase and splicing-reporter assays; ubiquitylation, fractionation, IL-6 reporter, EMT assays; ThT aggregation, MD, phase-separation microscopy","pmids":["36611919","36261009","35643629"],"confidence":"Medium","gaps":["Physiological balance between TAF15 activator and SRPK1-inhibitor roles unclear","Whether SGYS-driven aggregation matches ex vivo filament core not yet linked"]},{"year":2023,"claim":"Cryo-EM of patient filaments and oncogenic transcription studies resolved the disease-defining question and expanded TAF15's promoter-bound activator role, establishing TAF15 LCD residues 7–99 as the FTLD amyloid fold and showing direct activation of FASN, SOCS1, and NF-κB programs.","evidence":"Cryo-EM of ex vivo brain filaments; CUT&Tag, luciferase, Co-IP, CRISPR KO and in vivo mouse/cell models","pmids":["38057661","37183512","41244301"],"confidence":"High","gaps":["Trigger converting soluble TAF15 to filaments in vivo unknown","Sequence specificity of promoter binding not structurally defined"]},{"year":2024,"claim":"PKA phosphorylation and CypA stabilization addressed additional control of TAF15 RNA-binding and stability, showing PKA retunes transcript binding and CypA suppresses proteasomal degradation while promoting nuclear localization.","evidence":"iCLIP with cAMP activation; Co-IP, MS, proteasome inhibition, fractionation","pmids":["38568213","39402372"],"confidence":"Medium","gaps":["Phosphosites and direct downstream functional effects not mapped","CypA/TAF15 loop validated in single cancer context"]},{"year":2025,"claim":"Phase-separation/hnRNPA0 and prion-propagation studies addressed how the LC domain links condensate formation to transcription and disease spread, showing the C-terminal LCD is necessary and sufficient for hnRNPA0-enhanced transcription and that TAF15 fibrils seed and propagate FUS-independently.","evidence":"Domain swaps, phosphomimic and ALS mutations, transcription/phase-separation assays; recombinant fibrils, biosensor propagation, patient-brain seeding (preprint)","pmids":["41085196","bio_10.1101_2025.11.17.688886"],"confidence":"Medium","gaps":["In vivo relevance of hnRNPA0 condensates untested","Prion-propagation evidence remains a preprint without peer review"]},{"year":2026,"claim":"FET redundancy imaging and expanded cryo-EM addressed TAF15's homeostatic and structural disease spectrum, showing TAF15 compensates for EWSR1 loss at nascent RNA and that multiple TAF15 filament folds, including a Y38C-variant-driven fold, define FTLD-FET subtypes.","evidence":"Acute EWSR1 depletion with nanoscale imaging (preprint); cryo-EM of 17 patient brains with genetic sequencing (preprint)","pmids":["42051291","41648099"],"confidence":"Low","gaps":["EWSR1-compensation finding is imaging-based inference in a single preprint","Functional impact of distinct filament folds on clinical phenotype unknown"]},{"year":null,"claim":"The physiological trigger that converts soluble, modification-regulated TAF15 into self-propagating amyloid filaments in human neurons, and how its transcription, RNA-processing, and condensate functions are integrated, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined in vivo nucleation trigger for filament formation","Mechanistic link between normal RNA/transcription roles and pathological aggregation unestablished","Therapeutic strategies targeting TAF15 aggregation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,9,12,13,26]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,16,24,25,28]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[9,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[20,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,4,8,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,8]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,24,25,28]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,13,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,22,23]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,17,27]}],"complexes":["TFIID","RNA polymerase II preinitiation complex","U1-TAF15 snRNP","FET heterocomplex (FUS/EWSR1/TAF15)"],"partners":["FUS","EWSR1","PRMT1","U1C","SRPK1","HNRNPA0","TBP","CYPA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16514","full_name":"Transcription initiation factor TFIID subunit 12","aliases":["Transcription initiation factor TFIID 20/15 kDa subunits","TAFII-20/TAFII-15","TAFII20/TAFII15"],"length_aa":161,"mass_kda":17.9,"function":"The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription (PubMed:33795473). TFIID recognizes and binds promoters with or without a TATA box via its subunit TBP, a TATA-box-binding protein, and promotes assembly of the pre-initiation complex (PIC) (PubMed:33795473). The TFIID complex consists of TBP and TBP-associated factors (TAFs), including TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:33795473). Component of the TATA-binding protein-free TAF complex (TFTC), the PCAF histone acetylase complex and the STAGA transcription coactivator-HAT complex (PubMed:10373431, PubMed:7729427, PubMed:8598932, PubMed:8663456, PubMed:9674425, PubMed:9885574)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16514/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAF15","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPA","stoichiometry":4.0},{"gene":"SNRPC","stoichiometry":4.0},{"gene":"COL4A3BP","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"GLUL","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2},{"gene":"ILF3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TAF15","total_profiled":1310},"omim":[{"mim_id":"612237","title":"CHONDROSARCOMA, EXTRASKELETAL MYXOID","url":"https://www.omim.org/entry/612237"},{"mim_id":"601574","title":"TAF15 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 68-KD; TAF15","url":"https://www.omim.org/entry/601574"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TAF15"},"hgnc":{"alias_symbol":["hTAFII68","RBP56","Npl3"],"prev_symbol":["TAF2N"]},"alphafold":{"accession":"Q16514","domains":[{"cath_id":"1.10.20.10","chopping":"55-132","consensus_level":"high","plddt":93.7394,"start":55,"end":132}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16514","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16514-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16514-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAF15","jax_strain_url":"https://www.jax.org/strain/search?query=TAF15"},"sequence":{"accession":"Q16514","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16514.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16514/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16514"}},"corpus_meta":[{"pmid":"8890175","id":"PMC_8890175","title":"hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8890175","citation_count":299,"is_preprint":false},{"pmid":"18620564","id":"PMC_18620564","title":"The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response.","date":"2008","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18620564","citation_count":275,"is_preprint":false},{"pmid":"21856723","id":"PMC_21856723","title":"FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations.","date":"2011","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21856723","citation_count":245,"is_preprint":false},{"pmid":"9488465","id":"PMC_9488465","title":"EWS, but not EWS-FLI-1, is associated with both TFIID and RNA polymerase II: interactions between two members of the TET family, EWS and hTAFII68, and subunits of TFIID and RNA polymerase II complexes.","date":"1998","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9488465","citation_count":227,"is_preprint":false},{"pmid":"21438137","id":"PMC_21438137","title":"Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis.","date":"2011","source":"American journal of medical genetics. 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TBP-associated factor that co-purifies with a subpopulation of TFIID complexes and also co-purifies with RNA polymerase II, entering the preinitiation complex together with Pol II. The protein contains a consensus RNA-binding domain (RNP-CS) and binds both RNA and single-stranded DNA.\",\n      \"method\": \"Biochemical co-purification, RNA/ssDNA binding assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution and co-purification with multiple orthogonal approaches; foundational paper independently replicated by subsequent work\",\n      \"pmids\": [\"8890175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TAF15 (hTAFII68) interacts with specific TFIID subunits and specific subunits of RNA polymerase II. In vitro binding studies showed EWS and TAF15 interact with the same TFIID subunits, suggesting their presence in the same TFIID complex is mutually exclusive.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation from nuclear extracts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays with defined subunits plus co-purification; replicated and extended findings from the 1996 EMBO paper\",\n      \"pmids\": [\"9488465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TAF15 is present in both the nucleus and cytoplasm of most cell types. FET proteins (including TAF15) are targeted to stress granules induced by heat shock and oxidative stress. TAF15 (and FUS) were also detected in spreading initiation centers of adhering cells.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, live-cell imaging in multiple human cell types\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments across multiple cell types with functional context (stress response, cell spreading); single study\",\n      \"pmids\": [\"18620564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endogenous TAF15 is methylated in vivo at its RGG repeats by PRMT1. PRMT1 was identified as a TAF15-interacting protein and the major PRMT responsible for this methylation. Methylation of the RGG-containing C-terminus affects TAF15 subcellular localization (nucleus-cytoplasm shuttling) and is required for TAF15 to positively regulate expression of its target genes.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, subcellular fractionation, gene expression analysis after PRMT1 inhibition/knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation assay plus Co-IP plus functional readout (target gene regulation), multiple orthogonal methods in one study\",\n      \"pmids\": [\"19124016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A fraction of TAF15 specifically associates with human U1 snRNA to form a novel U1-TAF15 snRNP that is distinct from the canonical spliceosomal U1-Sm snRNP (none of the known Sm or U1-specific proteins co-precipitate). The U1-TAF15 snRNP tightly associates with chromatin in an RNA-dependent manner and accumulates in nucleolar caps upon transcriptional inhibition. The Sm-binding motif of U1 snRNA is essential for biogenesis of both U1-Sm and U1-TAF15 snRNPs.\",\n      \"method\": \"RNA immunoprecipitation, chromatin fractionation, transcription inhibition experiments, mutational analysis of U1 snRNA\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods (co-IP, chromatin fractionation, mutagenesis) establishing a novel RNP complex in one rigorous study\",\n      \"pmids\": [\"19282884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In FTLD-FUS (but not ALS-FUS-mutation cases), all endogenous FET proteins including TAF15 and EWS shift to insoluble fractions. Cell culture experiments showed that inhibition of Transportin-mediated nuclear import recruits all endogenous FET proteins (including TAF15) into cytoplasmic stress granules, mimicking the FTLD finding.\",\n      \"method\": \"Immunoblot of post-mortem tissue fractions, cell culture experiments with Transportin inhibition, immunohistochemistry\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation of human tissue plus cell culture mechanistic experiment with defined inhibitor; single lab\",\n      \"pmids\": [\"21856723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A fraction of nuclear TAF15 associates with the spliceosomal U1 snRNP complex, as demonstrated by co-precipitation of U1 snRNA, U1-70K, and Sm proteins. Pull-down assays showed a direct protein-protein interaction between TAF15 and U1C that required the N-terminal domain of TAF15. In vivo UV cross-linking showed TAF15 directly contacts RNA (likely Pol II transcripts).\",\n      \"method\": \"Immunoprecipitation from HeLa nuclear extracts, pull-down with recombinant proteins, UV cross-linking\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus recombinant protein pull-down plus in vivo UV crosslinking; single lab\",\n      \"pmids\": [\"22019700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TAF15 knockdown affects expression of genes involved in cell cycle and apoptosis, causes growth inhibition and increased apoptosis. TAF15 regulates cell cycle genes post-transcriptionally through a pathway involving miRNAs from the onco-miR-17 locus (miR-17-5p and miR-20a), which in turn control CDKN1A/p21 levels. TAF15 depletion decreases levels of miR-17-5p and miR-20a.\",\n      \"method\": \"siRNA knockdown, global gene expression profiling, miRNA quantification, cell proliferation/apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined phenotypic readout plus miRNA profiling; single lab, multiple methods\",\n      \"pmids\": [\"23128393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The C-terminal RGG domain of TAF15 is responsible for shuttling between the nucleus and cytoplasm. A transportin-dependent nuclear localization signal (NLS) resides at the C-terminus. TAF15 localization was shown to depend on ongoing transcription, and independent domains engage in nucleolar capping upon transcription inhibition. TAF15 localization is differentially regulated in HeLa versus neuronal HT22 cells.\",\n      \"method\": \"Domain deletion constructs, GFP fusions, transportin inhibition assays, transcription inhibition experiments, subcellular fractionation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping with multiple constructs plus pharmacological perturbations; single lab\",\n      \"pmids\": [\"22771914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TAF15 binds to conserved RNA targets in human brain and mouse neurons enriched in transcripts encoding synaptic proteins. TAF15 is required for a critical alternative splicing event of the Grin1 (NMDA receptor NR1 subunit) that controls NR1 activity and trafficking. Unlike FUS and TDP-43, TAF15 has a minimal role in general alternative splicing.\",\n      \"method\": \"HITS-CLIP, RNA-seq, siRNA knockdown in neurons, splicing analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — HITS-CLIP plus RNA-seq plus KD with specific splicing readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23416048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FUS, EWSR1, and TAF15 form homo- and heterocomplexes via a conserved N-terminal motif (FETBM1). This interaction is RNA- and DNA-independent and robust up to 1M NaCl. The FETBM1 motif is also required for binding of normal full-length FET proteins to their oncogenic fusion proteins.\",\n      \"method\": \"Recombinant protein pulldown, mass spectrometry, mutagenesis of FETBM1 motif\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant protein reconstitution plus mutagenesis plus MS; multiple orthogonal methods in one study\",\n      \"pmids\": [\"23975937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TAF15 selectively co-immunoprecipitates with the higher molecular weight hnRNP M3/4 isoforms (contrasting with FUS which prefers hnRNP M1/2). This association is mediated through direct protein-protein interactions via the amino-termini of the TET proteins, independently of RNA.\",\n      \"method\": \"Co-immunoprecipitation from HeLa nuclear extracts, recombinant protein pulldown, immunofluorescence co-localization\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RNA-independent direct pulldown; single lab\",\n      \"pmids\": [\"24474660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The solution NMR structure of the TAF15 RRM domain was determined. RNA binding occurs through a non-canonical mode: rather than classical stacking interactions between nitrogen bases and aromatic amino acids at RNP sites, moderate-affinity hydrogen bonding between stem-loop RNA bases and a concave face on the RRM surface primarily mediates the interaction. RNA binding depends on structural elements in the RNA rather than sequence alone.\",\n      \"method\": \"Solution NMR spectroscopy, isothermal titration calorimetry, docking, molecular dynamics simulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure determination plus calorimetric binding measurements plus MD simulation; multiple orthogonal methods\",\n      \"pmids\": [\"26612539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TAF15 binds ~4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns and are enriched in 3' UTRs. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. Unlike FUS and TDP-43, TAF15 has minimal role in alternative splicing.\",\n      \"method\": \"CLIP-seq, RNA Bind-N-Seq, RNA-seq in motor neurons and neural progenitors, double KO analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent binding technologies (CLIP-seq + RBNS) plus loss-of-function RNA-seq; replicated across multiple cell types\",\n      \"pmids\": [\"27378374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAF15 low-complexity (LC) domain forms amyloid-like hydrogel fibrils that bind the CTD of RNA polymerase II. NMR and FRAP showed that heptad positions far from the acidic C-terminal tail of RNA pol II CTD bind TAF15 fibrils most avidly. Mutation of CTD lysines at heptad position 7 to consensus serines reduced TAF15 fibril binding, implicating electrostatic interactions in complex formation.\",\n      \"method\": \"NMR spectroscopy (spin relaxation, dark-state exchange saturation transfer), hydrogel fibril FRAP assay, site-directed mutagenesis of CTD lysines\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR plus functional fibril-binding assay plus mutagenesis; multiple orthogonal methods\",\n      \"pmids\": [\"28945358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRMT1 shows differential interaction with RGG-boxes of TAF15 compared to FUS and EWS. The Asp residue in TAF15's YGGDR(S/G)G repeats confers poor binding to PRMT1, resulting in reduced overall methylation of TAF15 compared to other FET proteins.\",\n      \"method\": \"Peptide-based polyRGG substrate assays, novel 2-hybrid binding assay\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — biochemical peptide binding assay and 2-hybrid; single lab, limited cellular validation\",\n      \"pmids\": [\"29193371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAF15 is phosphorylated on tyrosine residue(s) by v-Src kinase in vitro and in vivo. TAF15 associates with the SH3 domains of v-Src and other cell signaling proteins. Full-length v-Src stimulates TAF15-mediated transcriptional activation, while dominant-negative Src reduces it in a dose-dependent fashion.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation with SH3 domains, transcriptional reporter assays, dominant-negative overexpression\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus Co-IP plus transcriptional reporter; multiple methods, single lab\",\n      \"pmids\": [\"15094065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In a Drosophila model, parkin directly binds to TAF15. Parkin overexpression suppresses TAF15-induced toxicity (defective lifespan and locomotion), and overexpression of parkin in neuronal cells reduces TAF15 protein levels through parkin's E3 ubiquitin ligase activity.\",\n      \"method\": \"Co-immunoprecipitation in Drosophila, genetic overexpression/loss-of-function, western blot quantification of TAF15 levels\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo genetic rescue plus protein level assay; Drosophila model, single lab\",\n      \"pmids\": [\"30339961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GSK-3β (Shaggy) is abnormally activated in neurons of TAF15-expressing Drosophila. GSK-3β inhibition (pharmacological or genetic) reduces TAF15 protein levels and suppresses TAF15-induced neurotoxicity. The SCF-Slimb E3 ubiquitin ligase complex genetically interacts with TAF15 and is critical for GSK-3β-mediated suppression of TAF15 toxicity.\",\n      \"method\": \"Transgenic Drosophila model, pharmacological GSK-3β inhibition (lithium), genetic epistasis with F-box proteins, western blot, immunohistochemistry\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus pharmacological inhibition plus protein level assay in vivo; single lab, Drosophila model\",\n      \"pmids\": [\"32915460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Xenopus tropicalis, Taf15 regulates dorsoanterior neural development through two distinct mechanisms on a single target fgfr4: (1) maternal+zygotic Taf15 depletion causes intron retention in fgfr4, and (2) depletion of zygotic Taf15 alone reduces total fgfr4 transcript levels, indicating both post-transcriptional and transcriptional modes of regulation.\",\n      \"method\": \"Morpholino/CRISPR depletion in Xenopus, RNA-seq for exon usage and transcript abundance, epistasis with fgfr4 and ventx2.1\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in vivo with RNA-seq identifying two distinct mechanisms; single lab, Xenopus ortholog\",\n      \"pmids\": [\"34345915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminal RGG domain of TAF15 associates with SRPK1, downregulates SRPK1 kinase activity, partially relocalizes SRPK1 to the nucleus, and results in hypophosphorylation of SR proteins, inhibition of pre-mRNA splicing of a reporter minigene, and inhibition of Lamin B receptor phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assay, reporter minigene splicing assay, western blot for SR protein phosphorylation, fluorescence microscopy\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus enzymatic activity assay plus functional splicing reporter; single lab, multiple methods\",\n      \"pmids\": [\"36611919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TIF1γ binds TBP in competition with TAF15 and impedes TAF15/TBP-mediated IL-6 transactivation. TIF1γ modifies TAF15 through multi-mono-ubiquitylation and drives nuclear export of TAF15. TAF15/TBP complex activity is required for IL-6 activation-induced EMT and invasion of lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation in human cell lines, ubiquitylation assay, nuclear/cytoplasmic fractionation, luciferase reporter for IL-6 transactivation, EMT/invasion assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitylation assay plus fractionation plus transcriptional reporter; single lab\",\n      \"pmids\": [\"36261009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The SGYS motif within the TAF15 prion-like domain (PrLD) is a critical segment for amyloid fibril formation. ALS-associated mutation E71G in the T2 segment (Y56GQSQSGYSQSYGGYENQ73) significantly enhances aggregation. The T2 peptide with strong β-amyloid-forming tendency can induce liquid-to-solid phase transition of TAF15-PrLD protein. The SGYS motif maintains a stable β-sheet through intermolecular hydrogen bonds and π-π stacking.\",\n      \"method\": \"Thioflavin T aggregation assay, molecular dynamics simulation, mutagenesis, phase separation microscopy\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical aggregation assay plus MD simulation plus mutagenesis; multiple methods, single lab\",\n      \"pmids\": [\"35643629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of TAF15 amyloid filaments extracted from FTLD-FUS patient brains were determined. The filament fold is formed from residues 7–99 in the low-complexity domain (LCD) of TAF15, was identical among four individuals, and the same fold was found in motor cortex and brainstem of two individuals with upper/lower motor neuron pathology. This establishes TAF15 (not FUS) as the primary amyloid-forming protein in FTLD-FUS (now FTLD-TAF15).\",\n      \"method\": \"Cryo-electron microscopy of ex vivo amyloid filaments from post-mortem human brain\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of ex vivo material from four independent patients with identical fold; replicated across multiple brain regions\",\n      \"pmids\": [\"38057661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAF15 directly binds the promoter region of FASN to facilitate its transcription, promoting lipid steatosis. TAF15 also interacts with p65 (NF-κB subunit) and activates NF-κB signaling, increasing proinflammatory cytokine secretion and triggering M1 macrophage polarization. Both effects were shown in hepatocyte-specific AAV-knockdown and overexpression mouse models of NASH.\",\n      \"method\": \"CUT&Tag, dual-luciferase reporter assay, co-immunoprecipitation, immunofluorescence, hepatocyte-specific AAV knockdown/overexpression in mice\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-like CUT&Tag plus luciferase reporter plus Co-IP plus in vivo mouse model; single lab\",\n      \"pmids\": [\"37183512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TAF15 in tumor-associated macrophages transcriptionally activates SOCS1, thereby inhibiting the JAK2/STAT1 signaling pathway and suppressing M1 macrophage polarization, promoting M2 polarization and ICC progression.\",\n      \"method\": \"CUT&Tag, dual-luciferase reporter assay, CRISPR-Cas9 TAF15 knockout in THP-1 cells, in vitro co-culture, in vivo M2pepLNP-siTAF15 treatment\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag plus luciferase plus CRISPR KO plus in vivo; single lab\",\n      \"pmids\": [\"41244301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAF15 is a nuclear substrate of PKA. PKA-mediated phosphorylation of TAF15 alters its binding to target transcripts related to mRNA maturation, splicing, and protein-binding functions, as shown by iCLIP experiments comparing phosphorylated vs. unphosphorylated TAF15.\",\n      \"method\": \"iCLIP (crosslinking immunoprecipitation), PKA substrate identification, cAMP pathway activation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iCLIP with pathway perturbation; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"38568213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CypA interacts with TAF15, stabilizes it by suppressing proteasomal degradation, and promotes its nuclear localization. TAF15 in turn positively regulates STAT5A. This forms a CypA/TAF15/STAT5A/miR-514a-3p feedback loop driving EMT in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, proteasome inhibition assay, subcellular fractionation, western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS plus functional rescue; single lab\",\n      \"pmids\": [\"39402372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAF15's C-terminal low-complexity (LC) domain undergoes phase separation and mediates dynamic interactions with hnRNPA0, which enhances TAF15's transcriptional activity. Domain-swapping with FUS showed the C-terminal LC domain is both necessary and sufficient for hnRNPA0 responsiveness. Phosphomimic mutations in the C-terminal LC domain disrupt hnRNPA0 interaction. ALS-linked mutations in TAF15 impair phase separation, reduce hnRNPA0 binding, and eliminate transcriptional enhancement.\",\n      \"method\": \"Domain-swap experiments, phosphomimic mutagenesis, ALS-linked point mutations, transcriptional reporter assays, phase separation microscopy\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutational analyses plus functional transcription assay plus phase separation microscopy; single lab\",\n      \"pmids\": [\"41085196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TAF15 is specifically cleaved by caspases-3 and -7 at the consensus sequence 106DQPD/Y110. Site-directed mutagenesis confirmed this as the sole caspase-3/7 cleavage site. TAF15 was cleaved at more than one site in staurosporine-treated Jurkat cells, suggesting additional proteolytic regulation in apoptosis.\",\n      \"method\": \"In vitro caspase cleavage assay, site-directed mutagenesis, cell-based apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay plus site-directed mutagenesis; single lab\",\n      \"pmids\": [\"19426707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAF15 forms amyloid fibrils under physiological conditions that propagate in a prion-like fashion between cells. Patient-derived TAF15 aggregates from aFTLD-U brains seed aggregation and transmit serially between cells. Seeding is specific to TAF15 and does not cross-seed with FUS. Computational and peptide mapping identified multiple aggregation-prone regions in the TAF15 low-complexity domain that coincide with ex vivo filament core hotspots.\",\n      \"method\": \"Recombinant fibril formation, single-fluorophore biosensor for cellular propagation, patient brain extract seeding, peptide aggregation mapping, computational prediction\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — recombinant fibril assay plus patient material seeding plus cellular propagation assay; preprint, not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.17.688886\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Acute depletion of EWSR1 induces compensatory reorganization of both FUS and TAF15 to closely resemble EWSR1's organization with nascent RNA, demonstrating functional redundancy within the FET family for homeostatic regulation of nascent RNA levels. Nanoscale imaging showed TAF15 redistributes to enhance clustering with newly synthesized RNA upon EWSR1 loss.\",\n      \"method\": \"Acute EWSR1 depletion, nanoscale fluorescence imaging, nascent RNA labeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — imaging-based localization with functional inference; preprint, single lab\",\n      \"pmids\": [\"42051291\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"All three proposed subtypes of FTLD-FET (aFTLD-U, NIFID, BIBD) are characterized by TAF15 amyloid filaments (not FUS filaments). Four distinct TAF15 filament folds were identified among NIFID cases and distinct folds for BIBD cases. A TAF15 Y38C variant was found in one BIBD case whose filament fold cannot incorporate wild-type TAF15 despite heterozygosity, suggesting this variant drives TAF15 filament assembly.\",\n      \"method\": \"Cryo-EM structure determination from post-mortem brain tissue of 17 individuals; genetic sequencing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures from 17 independent cases with genetic variant analysis; preprint, extends peer-reviewed 2023 Nature paper\",\n      \"pmids\": [\"41648099\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TAF15 is a multifunctional FET-family RNA/ssDNA-binding protein that associates with subpopulations of TFIID and RNA polymerase II to participate in transcription initiation; its RGG-rich C-terminal low-complexity domain undergoes arginine methylation by PRMT1 (regulating subcellular localization and gene activation), tyrosine phosphorylation by Src, and serine phosphorylation by PKA (altering RNA-binding specificity), and forms amyloid-like assemblies that bind the RNA pol II CTD via electrostatic interactions with specific CTD lysines; the RRM domain recognizes RNA stem-loops through a non-canonical hydrogen-bonding mode; TAF15 forms homo- and hetero-complexes with FUS and EWSR1 via a conserved N-terminal FETBM1 motif, associates with a distinct U1-TAF15 snRNP and with spliceosomal U1C protein, regulates alternative splicing of neuronal targets (notably Grin1) and mRNA stability, controls cell proliferation through a miR-17 locus–CDKN1A axis, and in disease conditions assembles into structurally defined amyloid filaments (low-complexity domain residues 7–99) that propagate in a prion-like manner and constitute the primary pathological aggregates in FTLD-TAF15.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAF15 is a multifunctional FET-family RNA/single-stranded-DNA-binding protein that couples transcription to RNA processing and, in disease, becomes the principal amyloid-forming species in frontotemporal lobar degeneration [#0, #23]. It was first isolated as a TBP-associated factor that co-purifies with a subpopulation of TFIID and enters the RNA polymerase II preinitiation complex, binding both RNA and ssDNA through a consensus RNA-binding domain [#0, #1]. Its RRM engages target RNAs through a non-canonical hydrogen-bonding mode that reads RNA stem-loop structure rather than sequence alone [#12], and transcriptome-wide it binds thousands of structured, GGUA-enriched transcripts—enriched for synaptic mRNAs—where it controls RNA turnover and a specific Grin1 alternative-splicing event, while contributing minimally to global splicing [#9, #13]. TAF15 assembles into homo- and hetero-complexes with FUS and EWSR1 via a conserved, RNA-independent N-terminal FETBM1 motif [#10], and a fraction associates with U1 snRNP through direct contact with U1C to form a distinct U1-TAF15 snRNP [#4, #6]. Its activity is governed by extensive post-translational modification of the RGG-rich C-terminal low-complexity domain: PRMT1-mediated arginine methylation regulating shuttling and target-gene activation [#3], Src tyrosine phosphorylation enhancing transcriptional activation [#16], and PKA serine phosphorylation that retunes RNA-binding specificity [#26]. The same low-complexity domain phase-separates and forms amyloid-like fibrils that bind the RNA polymerase II CTD through electrostatic contacts with heptad-position lysines [#14, #28]. In FTLD, TAF15 low-complexity-domain residues 7\\u201399 fold into structurally defined amyloid filaments that are identical across patients, establishing TAF15 rather than FUS as the primary pathological aggregate in FTLD-TAF15 [#23]. TAF15 also functions as a sequence-specific promoter-binding transcriptional activator in cancer and metabolic contexts, driving FASN, SOCS1, and NF-\\u03baB-dependent programs [#24, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing TAF15's biochemical identity answered whether it was a transcription factor, showing it is a TBP-associated factor bridging TFIID and Pol II that also binds nucleic acids.\",\n      \"evidence\": \"Biochemical co-purification with TFIID and Pol II plus RNA/ssDNA binding assays\",\n      \"pmids\": [\"8890175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which promoters or genes depend on TAF15\", \"RNA-binding specificity unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping TAF15 and EWS contacts within TFIID addressed how FET proteins partition among basal machinery, indicating mutually exclusive incorporation into TFIID.\",\n      \"evidence\": \"In vitro binding assays and Co-IP with defined TFIID and Pol II subunits\",\n      \"pmids\": [\"9488465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of mutual exclusivity untested\", \"Stoichiometry in vivo unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localization and methylation studies addressed how TAF15 trafficking is controlled, identifying PRMT1 as the RGG arginine methyltransferase that governs nucleocytoplasmic shuttling and target-gene activation, and placing TAF15 in stress granules.\",\n      \"evidence\": \"Immunofluorescence/fractionation across cell types; Co-IP, in vitro methylation, gene expression after PRMT1 perturbation\",\n      \"pmids\": [\"18620564\", \"19124016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific methylated arginines not all mapped\", \"Link between methylation and stress-granule recruitment unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery of a U1-TAF15 snRNP and caspase cleavage addressed how TAF15 connects to splicing machinery and apoptotic regulation, defining a non-canonical chromatin-associated U1 particle and a caspase-3/7 cleavage site.\",\n      \"evidence\": \"RNA-IP, chromatin fractionation, U1 mutagenesis; in vitro caspase cleavage with site-directed mutagenesis\",\n      \"pmids\": [\"19282884\", \"19426707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the U1-TAF15 snRNP not established\", \"Biological role of caspase cleavage fragment unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"FTLD fractionation and the U1C interaction addressed the disease relevance and spliceosomal coupling of TAF15, showing FET-protein insolubility in FTLD-FUS and a direct N-terminal TAF15\\u2013U1C contact.\",\n      \"evidence\": \"Post-mortem tissue immunoblot, Transportin-inhibition cell models; reciprocal Co-IP, recombinant pulldown, UV crosslinking\",\n      \"pmids\": [\"21856723\", \"22019700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAF15 or FUS is the primary aggregate not yet resolved in 2011\", \"Direct RNA targets in vivo incompletely defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain mapping and the miR-17/CDKN1A work addressed how TAF15 controls its own localization and cell proliferation, defining a C-terminal transportin-dependent NLS and a post-transcriptional growth-control axis.\",\n      \"evidence\": \"GFP-fusion domain deletions with transportin/transcription inhibition; siRNA knockdown with gene/miRNA profiling and proliferation assays\",\n      \"pmids\": [\"22771914\", \"23128393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TAF15 controls miR-17 locus unknown\", \"Cell-type-specific localization rules not generalized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"CLIP-based target identification and FET heterocomplex mapping addressed what RNAs TAF15 regulates and how FET proteins assemble, defining synaptic-transcript binding, a specific Grin1 splicing role, and the RNA-independent FETBM1 interaction motif.\",\n      \"evidence\": \"HITS-CLIP, RNA-seq, neuronal knockdown; recombinant pulldown, mass spectrometry, FETBM1 mutagenesis\",\n      \"pmids\": [\"23416048\", \"23975937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of most bound transcripts untested\", \"Whether FET heterocomplexes act in transcription or RNA processing not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The hnRNP M isoform-selective interaction addressed how individual FET proteins acquire distinct partnerships, showing TAF15 preferentially binds hnRNP M3/4 via its amino-terminus.\",\n      \"evidence\": \"Co-IP, recombinant pulldown, immunofluorescence co-localization\",\n      \"pmids\": [\"24474660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional outcome of the TAF15\\u2013hnRNP M complex unknown\", \"Single lab without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The RRM solution structure addressed the molecular basis of TAF15 RNA recognition, revealing a non-canonical hydrogen-bonding interface that reads RNA structure rather than sequence.\",\n      \"evidence\": \"Solution NMR, ITC, docking and molecular dynamics\",\n      \"pmids\": [\"26612539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of structure-based recognition not tested\", \"Contribution of RGG domain to RNA affinity not modeled here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genome-wide binding in brain addressed TAF15's transcriptome-scale function, confirming GGUA-motif binding, 3'UTR enrichment, RNA-turnover control shared with FUS, and minimal splicing role.\",\n      \"evidence\": \"CLIP-seq, RNA Bind-N-Seq, RNA-seq, double knockout\",\n      \"pmids\": [\"27378374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking binding to turnover unresolved\", \"Redundancy boundaries with FUS not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"LC-domain fibril and PRMT1-selectivity studies addressed how TAF15 engages the Pol II CTD and why it is hypomethylated, defining electrostatic CTD-lysine contacts and a methylation-limiting Asp in its RGG repeats.\",\n      \"evidence\": \"NMR, hydrogel fibril FRAP, CTD lysine mutagenesis; peptide polyRGG assays and 2-hybrid binding\",\n      \"pmids\": [\"28945358\", \"29193371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CTD-fibril binding occurs at native concentrations in cells untested\", \"Consequence of reduced methylation for TAF15 function not directly shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Src phosphorylation and Drosophila parkin work addressed signaling control and turnover of TAF15, showing tyrosine phosphorylation enhances transcriptional activation and parkin ubiquitin-ligase activity lowers TAF15 levels and toxicity.\",\n      \"evidence\": \"In vitro kinase and SH3 Co-IP with reporter assays; Drosophila Co-IP, genetic rescue, protein-level westerns\",\n      \"pmids\": [\"15094065\", \"30339961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylated residues and direct transcriptional mechanism not mapped\", \"Parkin\\u2013TAF15 relationship not confirmed in mammalian neurons\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"GSK-3\\u03b2/SCF-Slimb genetics addressed the degradation pathway controlling TAF15 toxicity, showing kinase activation and an E3 ligase complex modulate TAF15 levels and neurotoxicity.\",\n      \"evidence\": \"Transgenic Drosophila, lithium inhibition, F-box epistasis, westerns and immunohistochemistry\",\n      \"pmids\": [\"32915460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation of TAF15 by GSK-3\\u03b2 not demonstrated\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Xenopus depletion addressed TAF15's developmental role, showing it regulates a single target (fgfr4) through both intron retention and transcript-abundance control during neural development.\",\n      \"evidence\": \"Morpholino/CRISPR depletion, RNA-seq exon/abundance analysis, epistasis\",\n      \"pmids\": [\"34345915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether dual regulation generalizes beyond fgfr4 unknown\", \"Ortholog-specific; mammalian developmental role untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SRPK1, TIF1\\u03b3, and PrLD aggregation studies addressed how TAF15 modulates splicing kinases, how it is competitively regulated at TBP, and what drives its aggregation, defining SRPK1 inhibition, TIF1\\u03b3-mediated ubiquitylation/export, and an SGYS \\u03b2-amyloid motif sensitized by ALS mutation E71G.\",\n      \"evidence\": \"Co-IP, kinase and splicing-reporter assays; ubiquitylation, fractionation, IL-6 reporter, EMT assays; ThT aggregation, MD, phase-separation microscopy\",\n      \"pmids\": [\"36611919\", \"36261009\", \"35643629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological balance between TAF15 activator and SRPK1-inhibitor roles unclear\", \"Whether SGYS-driven aggregation matches ex vivo filament core not yet linked\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM of patient filaments and oncogenic transcription studies resolved the disease-defining question and expanded TAF15's promoter-bound activator role, establishing TAF15 LCD residues 7\\u201399 as the FTLD amyloid fold and showing direct activation of FASN, SOCS1, and NF-\\u03baB programs.\",\n      \"evidence\": \"Cryo-EM of ex vivo brain filaments; CUT&Tag, luciferase, Co-IP, CRISPR KO and in vivo mouse/cell models\",\n      \"pmids\": [\"38057661\", \"37183512\", \"41244301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger converting soluble TAF15 to filaments in vivo unknown\", \"Sequence specificity of promoter binding not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"PKA phosphorylation and CypA stabilization addressed additional control of TAF15 RNA-binding and stability, showing PKA retunes transcript binding and CypA suppresses proteasomal degradation while promoting nuclear localization.\",\n      \"evidence\": \"iCLIP with cAMP activation; Co-IP, MS, proteasome inhibition, fractionation\",\n      \"pmids\": [\"38568213\", \"39402372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites and direct downstream functional effects not mapped\", \"CypA/TAF15 loop validated in single cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Phase-separation/hnRNPA0 and prion-propagation studies addressed how the LC domain links condensate formation to transcription and disease spread, showing the C-terminal LCD is necessary and sufficient for hnRNPA0-enhanced transcription and that TAF15 fibrils seed and propagate FUS-independently.\",\n      \"evidence\": \"Domain swaps, phosphomimic and ALS mutations, transcription/phase-separation assays; recombinant fibrils, biosensor propagation, patient-brain seeding (preprint)\",\n      \"pmids\": [\"41085196\", \"bio_10.1101_2025.11.17.688886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of hnRNPA0 condensates untested\", \"Prion-propagation evidence remains a preprint without peer review\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"FET redundancy imaging and expanded cryo-EM addressed TAF15's homeostatic and structural disease spectrum, showing TAF15 compensates for EWSR1 loss at nascent RNA and that multiple TAF15 filament folds, including a Y38C-variant-driven fold, define FTLD-FET subtypes.\",\n      \"evidence\": \"Acute EWSR1 depletion with nanoscale imaging (preprint); cryo-EM of 17 patient brains with genetic sequencing (preprint)\",\n      \"pmids\": [\"42051291\", \"41648099\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"EWSR1-compensation finding is imaging-based inference in a single preprint\", \"Functional impact of distinct filament folds on clinical phenotype unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological trigger that converts soluble, modification-regulated TAF15 into self-propagating amyloid filaments in human neurons, and how its transcription, RNA-processing, and condensate functions are integrated, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined in vivo nucleation trigger for filament formation\", \"Mechanistic link between normal RNA/transcription roles and pathological aggregation unestablished\", \"Therapeutic strategies targeting TAF15 aggregation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 9, 12, 13, 26]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 16, 24, 25, 28]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [20, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 4, 8, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 24, 25, 28]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 13, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 22, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 17, 27]}\n    ],\n    \"complexes\": [\n      \"TFIID\",\n      \"RNA polymerase II preinitiation complex\",\n      \"U1-TAF15 snRNP\",\n      \"FET heterocomplex (FUS/EWSR1/TAF15)\"\n    ],\n    \"partners\": [\n      \"FUS\",\n      \"EWSR1\",\n      \"PRMT1\",\n      \"U1C\",\n      \"SRPK1\",\n      \"hnRNPA0\",\n      \"TBP\",\n      \"CypA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}