{"gene":"NXF1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"TAP/NXF1 has a modular architecture comprising an RNP-type RNA-binding domain, four leucine-rich repeats (LRR), an NTF2-like domain that mediates heterodimerization with p15/NXT1, and a UBA-like domain that mediates interaction with FG-nucleoporins at the nuclear pore complex.","method":"Domain analysis, in vitro binding assays, functional export assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain dissection with multiple binding assays and functional validation, replicated across multiple studies","pmids":["11073998"],"is_preprint":false},{"year":2002,"finding":"The C-terminal UBA-like domain of NXF1/TAP has a four-helix bundle structure and mediates FG-nucleoporin binding; mutation F617A suppresses this interaction. The NTF2-like scaffold (heterodimerized with p15) provides a second nucleoporin-binding site, and both sites act synergistically; two copies of either domain alone are sufficient for directional mRNA export independent of p15.","method":"NMR structure determination; mutagenesis; Xenopus oocyte export assays","journal":"Nature structural biology / Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis in one study (PMID:11875519) and functional dissection confirmed in PMID:12101235","pmids":["11875519","12101235"],"is_preprint":false},{"year":2001,"finding":"Drosophila NXF1 (small bristles/sbr) and p15 are essential for nuclear export of the bulk of polyadenylated mRNAs (heat-shock and non-heat-shock, spliced and intronless) in Drosophila cells; depletion of NXF2–NXF4 has no equivalent phenotype.","method":"RNAi depletion in Drosophila S2 cells; fluorescence in situ hybridization (FISH) for poly(A)+ RNA","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with specific nuclear accumulation phenotype, replicated in two independent Drosophila studies (PMID:11780633, PMID:11780634)","pmids":["11780633","11780634"],"is_preprint":false},{"year":2004,"finding":"The nucleoporin RanBP2/Nup358 (cytoplasmic filaments of the NPC) provides a major binding site for NXF1-p15 dimers; depletion of RanBP2 causes NXF1 to redistribute to the cytoplasm and blocks mRNA export, whereas depletion of CAN/Nup214 blocks export without displacing NXF1, demonstrating specificity of the RanBP2–NXF1 interaction.","method":"RNAi depletion in Drosophila cells; immunofluorescence; FISH","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal RNAi comparisons with specific localization and export phenotypes, multiple orthogonal readouts","pmids":["14729961"],"is_preprint":false},{"year":2001,"finding":"NXF1/TAP is recruited to spliced mRNPs via a direct interaction with U2AF35 (small subunit of splicing factor U2AF); a distinct region of TAP mediates this interaction, which is evolutionarily conserved across metazoa and facilitates TAP's addition to mRNA substrates.","method":"Yeast two-hybrid; in vitro binding with recombinant proteins; co-immunoprecipitation; Xenopus oocyte export assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed in vitro and in cell context, single lab, two orthogonal methods","pmids":["11724776"],"is_preprint":false},{"year":2006,"finding":"The UBA domain of yeast Mex67 (NXF1 ortholog) directly interacts with polyubiquitin chains and with Hpr1 (a THO/TREX component that is regulated by ubiquitylation in a transcription-dependent manner), transiently protecting Hpr1 from proteasomal degradation and thereby recruiting the mRNA export machinery to transcribing genes.","method":"Chromatin immunoprecipitation; in vitro binding; mutagenesis; co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, in vitro binding, ubiquitin interaction assays) in a single focused study","pmids":["17056718"],"is_preprint":false},{"year":2007,"finding":"The yeast Mex67-Mtr2 heterodimer mediates nuclear export of 60S ribosomal subunits via a distinct loop-extended electrostatic surface on its NTF2-like scaffold that binds pre-60S particles and 5S rRNA; this surface is absent from human TAP-p15 and is separate from the mRNA export interface.","method":"Biochemical interaction assays; mutagenesis; yeast genetics; ribosome export assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus genetic epistasis, replicated in independent yeast studies","pmids":["17434126","22956913"],"is_preprint":false},{"year":2007,"finding":"Mex67-Mtr2 interacts with the Nup84 complex (a structural NPC module lacking FG repeats) through the same loop surface that recruits pre-60S particles; Nup85 is the direct contact subunit. This interaction is essential for mRNA export.","method":"Chemical crosslinking; in vitro competition assays; yeast genetic suppressor analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — crosslinking identified contact subunit, competition assay confirmed overlap, genetic suppression, single lab","pmids":["18046452"],"is_preprint":false},{"year":2012,"finding":"NXF1 uses an intramolecular interaction to autoinhibit its RNA-binding activity. The TREX subunits Aly and Thoc5 contact NXF1 and drive it into an open conformation that exposes its RNA-binding domain, licensing mRNA binding. Combined knockdown of Aly and Thoc5 markedly reduces NXF1-mRNA association and causes severe mRNA export block.","method":"Co-immunoprecipitation; RNA-binding assays; RNAi knockdown with mRNA export readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conformational activation mechanism supported by multiple biochemical and cellular assays, clear mechanistic model","pmids":["22893130"],"is_preprint":false},{"year":2016,"finding":"SR proteins (SRSF1-7) act as NXF1 export adaptors that bind mRNA at sites adjacent to NXF1-binding sites (co-binding). SRSF3 and SRSF7 each promote NXF1 recruitment to mRNA and couple alternative splicing and polyadenylation to NXF1-mediated export; SRSF3 is the most potent adaptor and confers sequence specificity to NXF1 binding in last exons.","method":"iCLIP (individual-nucleotide-resolution UV cross-linking and immunoprecipitation); siRNA knockdown; RNAseq","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptome-wide iCLIP with quantitative co-binding analysis plus functional export assays, multiple SR proteins tested in parallel","pmids":["26944680"],"is_preprint":false},{"year":2015,"finding":"Crystal structure (3.4 Å) of human NXF1 (RRM-LRR-NTF2-like domains) in complex with NXT1 reveals a domain-swapped dimer in which linkers between LRR and NTF2-like domains interact with NXT1, forming a 2-fold symmetric RNA-binding platform that facilitates recognition of the CTE RNA stem-loop and promotes its nuclear export.","method":"X-ray crystallography; biochemical binding assays; cell-based export assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with complementary biochemical and cellular validation","pmids":["25628361"],"is_preprint":false},{"year":2006,"finding":"NXF1/TAP directly interacts with the neuronal RNA-binding protein HuD (but not the ubiquitous HuR); HuD forms a ternary complex with TAP and RNA, suggesting HuD acts as a neuron-specific adaptor for NXF1-mediated export of AU-rich element-containing mRNAs.","method":"In vitro binding with recombinant proteins; ternary complex formation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding demonstrated, ternary complex shown, single lab","pmids":["15358174"],"is_preprint":false},{"year":2006,"finding":"RBM15 (OTT1) directly binds the RNA transport element RTE and interacts directly with NXF1 via its C-terminal region, functioning as a novel export adaptor that links RTE-containing mRNAs to the NXF1 export pathway.","method":"In vitro RNA binding; yeast two-hybrid; co-immunoprecipitation; tethering assay; siRNA knockdown with export readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding and protein-protein interaction demonstrated in vitro; functional tethering assay confirms export activity, single lab","pmids":["17001072"],"is_preprint":false},{"year":2009,"finding":"RBM15B/OTT3, like its paralog RBM15, directly interacts with NXF1 and Aly/REF via its C-terminal region, associates with the splicing factor compartment and nuclear envelope, and has post-transcriptional regulatory activity, functioning as an NXF1 cofactor.","method":"Co-immunoprecipitation; subcellular localization; mutational analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction mapped by mutagenesis and co-IP, functional context provided, single lab","pmids":["19586903"],"is_preprint":false},{"year":2010,"finding":"Arginine methylation of REF/ALY reduces its RNA-binding affinity without affecting its TAP/NXF1 interaction; this reduced RNA binding is required for efficient displacement of RNA from REF by TAP during the handover of mRNA to NXF1 for export.","method":"Mass spectrometry methylation mapping; in vitro binding assays; in vivo RNA-binding assays; mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — PTM sites mapped by MS, mechanistic handover tested by multiple orthogonal biochemical and cellular methods","pmids":["20129943"],"is_preprint":false},{"year":2011,"finding":"The nuclear protein Tpr restricts nuclear export of intron-retaining mRNAs that traffic through the NXF1/Nxt1 pathway; Tpr knockdown increases export and translation from a CTE-containing retained-intron reporter but has no effect on CRM1-pathway (Rev/RRE) export or completely spliced mRNA export.","method":"RNAi knockdown; reporter mRNA export/expression assays (CTE vs. RRE reporters); pathway-specific readouts","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using two pathway-specific reporters, clean knockdown, single lab","pmids":["21613532"],"is_preprint":false},{"year":2011,"finding":"NXF1 is imported into the nucleus via redundant karyopherin pathways (importin β, karyopherin β2/transportin, importin 4, importin 11, importin α). Two NLS epitopes in NXF1's N-terminal tail (an N-terminal basic segment and an R-X2-5-P-Y motif) provide the majority of binding energy; mutation of both NLS epitopes mislocalizes NXF1 to the cytoplasm and impairs mRNA export function.","method":"Biochemical binding assays; mutagenesis; cellular localization studies; functional export assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — five karyopherins tested biochemically, NLS epitopes mapped by mutagenesis, functional consequence demonstrated","pmids":["21965294"],"is_preprint":false},{"year":2019,"finding":"In yeast, Mex67 localizes constitutively to the NPC independently of mRNA, occupying FG-repeat binding sites; its essential export function is spatially restricted to the NPC, as a Mex67-Nup116 fusion that anchors Mex67 at the NPC rescues mex67Δ. Mex67 has little interaction with mRNA in the nucleus and receives export substrates at the NPC channel.","method":"Quantitative live-cell fluorescence microscopy (FRAP, single-molecule tracking); genetic rescue with nucleoporin fusion","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative live imaging plus genetic rescue experiment define spatial restriction of function","pmids":["31753862"],"is_preprint":false},{"year":2019,"finding":"NXF1 is required for mRNA release on the cytoplasmic side of the NPC but not for initial mRNP docking to the NPC. NXF1 occupies cytoplasmic-side positions within the NPC (superresolution microscopy), and its NPC localization is RNA-independent. Dbp5 helicase activity is required for mRNP release at the cytoplasmic face, a mechanism conserved between yeast and humans.","method":"Live-cell mRNA export block assays; superresolution microscopy; FLIM-FRET within single NPCs","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — superresolution localization combined with FLIM-FRET protein-protein interaction measurements within single NPCs","pmids":["31375530"],"is_preprint":false},{"year":2019,"finding":"NXF1 downregulation causes RNA Pol II accumulation at the 3' end of genes; NXF1 promotes usage of distal polyadenylation sites, generating long 3' UTR isoforms. NXF1 cooperates with the cleavage factor CFI-68 to facilitate nuclear export of long 3' UTR transcripts containing UGUA motifs.","method":"siRNA knockdown; RNA-seq; Pol II ChIP-seq; 3' end sequencing (APA profiling); co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide transcriptomic and Pol II ChIP approaches combined with biochemical co-IP, multiple orthogonal methods","pmids":["30819645"],"is_preprint":false},{"year":2020,"finding":"NXF1 is preferentially required for nuclear export of single-exon or few-exon transcripts with long exons or high A/U content, while TREX complex components preferentially facilitate export of spliced G/C-rich transcripts. Short sequence elements sufficient to confer NXF1-dependence were identified by massively parallel reporter assays.","method":"Quantitative RNA fractionation after siRNA depletion; massively parallel reporter assays; transcriptome-wide RNA localization profiling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptome-wide quantitative localization profiling combined with reporter assays, multiple export factors compared","pmids":["32504555"],"is_preprint":false},{"year":2017,"finding":"Mex67-Mtr2 (TAP-p15) cofunctions with Los1 (Exportin-t) in primary tRNA nuclear export in yeast; inactivation of Mex67 or Mtr2 causes nuclear accumulation of end-matured unspliced tRNAs, and Mex67 co-immunoprecipitates with tRNAs in vivo. Mex67-Mtr2 overexpression can substitute for Los1.","method":"Genetic inactivation; FISH for tRNA localization; in vivo co-immunoprecipitation; overexpression rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and biochemical approaches, genetic complementation, direct RNA-protein association shown","pmids":["29212662"],"is_preprint":false},{"year":2007,"finding":"The UBA domain of Mex67 has a classical three-helix UBA fold plus a fourth helix (H4) that acts as a molecular switch: H4 coordinates interaction with ubiquitin-bound Hpr1, selects for polyubiquitin, and prevents binding to non-specific substrates. Deletion or mutation of H4 strengthens ubiquitin binding but decreases Hpr1 affinity and reduces cotranscriptional Mex67 recruitment and mRNA export.","method":"NMR structure; mutagenesis; fluorescence-based binding assays; chromatin immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus mutagenesis plus ChIP, multiple orthogonal functional assays","pmids":["17475778"],"is_preprint":false},{"year":2009,"finding":"NMR solution structure of the Mex67 UBA domain complexed with an FXFG nucleoporin peptide shows that Hpr1 and FXFG nucleoporins bind overlapping sites on UBA-Mex67; FXFG binding prevents UBA-Mex67 from subsequently binding ubiquitin, whereas Hpr1 binding allows polyubiquitin interaction.","method":"NMR structure; FRET-based binding assays; NMR titration","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure of complex plus FRET and NMR titration, multiple orthogonal structural and biochemical methods","pmids":["19401465"],"is_preprint":false},{"year":2015,"finding":"Crystal structure (3.3 Å) of yeast Mex67(ΔUBA):Mtr2 shows the LRR domain has a defined spatial relationship to the NTF2-like region; the NTF2-like domain of Mex67:Mtr2 contributes directly to RNA binding, extending the mRNA-binding surface. RRM and UBA domains are more mobile.","method":"X-ray crystallography; SAXS; RNA-binding assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with SAXS and in vitro RNA-binding assays","pmids":["25618852"],"is_preprint":false},{"year":2015,"finding":"The TREX-2 complex (Sac3-Thp1-Sem1-Sus1-Cdc31) interacts with Mex67:Mtr2 through the Sac3 N-terminal region via phenylalanine-containing motifs that bind the Mex67 NTF2-like domain similarly to FG-nucleoporins; deletion of Sac3N causes mRNA export defects, placing TREX-2 as a concentrator of mRNPs at the NPC entrance.","method":"Crystal structure; in vitro reconstitution; yeast genetic growth and export assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus genetic functional validation","pmids":["26051714"],"is_preprint":false},{"year":2003,"finding":"A natural allele of mouse Nxf1 (Nxf1^CAST from Mus musculus castaneus) suppresses intronic endogenous retrovirus insertion-induced mutations (Pitpn^vb, Eya1^BOR) by increasing correctly spliced mRNA and decreasing aberrant alternatively processed RNA, linking the mRNA export receptor to pre-mRNA processing fidelity.","method":"Positional complementation cloning; congenic mouse genetics; RNA analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic positional cloning identifies the gene; congenic allele directly suppresses multiple independent mutations","pmids":["14517553"],"is_preprint":false},{"year":2009,"finding":"A single amino acid substitution E610G in Nxf1 (within the UBA domain region) is sufficient to recreate the quantitative genetic modifier activity of the Nxf1^CAST allele for IAP retrotransposon insertion-induced alternative splicing defects, as demonstrated by CRISPR/Cas9-mediated genome editing.","method":"CRISPR/Cas9 genome editing; genome-wide splicing-sensitive microarrays; gene-focused splicing assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — single amino acid change introduced by CRISPR in co-isogenic background with transcriptome-wide splicing validation","pmids":["25835743"],"is_preprint":false},{"year":2009,"finding":"Drosophila NXF1/sbr loss-of-function causes disruption of the meiotic spindle in females and formation of tripolar spindles during the first meiotic division; the sbr^5 lethal allele deletes 492 nucleotides removing residues within the NTF2-like domain.","method":"Genetic analysis of mutant alleles; cytological analysis of meiotic spindles; sequencing of sbr allele","journal":"Chromosome research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function phenotype in meiosis linked to specific domain deletion, single lab, single method","pmids":["19779841"],"is_preprint":false},{"year":2016,"finding":"An NXF1 isoform (short NXF1, sNxf1), translated from an intron-10-retaining mRNA exported via a CTE element, is highly expressed in hippocampal and neocortical neurons. sNxf1 localizes to RNA granules in neurites, forms heterodimers with full-length NXF1, and can replace NXT1 to enhance expression of CTE-containing mRNA and promote its association with polyribosomes.","method":"Immunofluorescence in rodent brain; subcellular fractionation; co-immunoprecipitation; reporter expression/polyribosome profiling assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neuronal expression confirmed, heterodimer and functional replacement shown biochemically, single lab","pmids":["27708137"],"is_preprint":false},{"year":2007,"finding":"NXF1 TAP/NXF1 directly interacts with the HSV-1 protein ICP27 via the C-terminus of ICP27 (with N-terminal contribution); this interaction is required for ICP27's cytoplasmic export and for efficient nuclear export of HSV-1 viral transcripts. Aly/REF is not required for ICP27 export despite being recruited to viral transcription sites.","method":"Co-immunoprecipitation; in vitro binding; siRNA knockdown; in situ hybridization","journal":"Journal of virology / Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding shown in vitro, functional consequence confirmed by siRNA knockdown and RNA export assays, replicated across multiple HSV studies","pmids":["15767397","19019956","19369354"],"is_preprint":false},{"year":2009,"finding":"The Epstein-Barr virus protein EB2 contains a CRM1-independent nuclear export signal (NES, aa 61–146) composed of arginine-rich domains that interact directly with TAP/NXF1 and mediate mRNA export; the NES fused to a heterologous protein can export MS2-tethered mRNA.","method":"Co-immunoprecipitation; tethering export assay; mutagenesis","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction mapped to specific domain, tethering assay demonstrates export activity, single lab","pmids":["19793817"],"is_preprint":false},{"year":2014,"finding":"The gammaretrovirus MLV (murine leukemia virus) contains a cis-acting cytoplasmic accumulation element (CAE) in the pol gene that binds NXF1 directly; NXF1 depletion abolishes CAE function and causes nuclear retention or degradation of both spliced and unspliced MLV RNA transcripts.","method":"siRNA knockdown; RNA immunoprecipitation; FISH; co-immunoprecipitation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein interaction shown, functional consequences of NXF1 loss confirmed by FISH and RIP, single lab","pmids":["24478440"],"is_preprint":false},{"year":2014,"finding":"HBV core protein (HBc) associates with TREX components and NXF1-p15 by co-immunoprecipitation, and interference with NXF1-p15 function causes nuclear accumulation of HBc. HBV pregenomic RNA (pgRNA) export to the cytoplasm is reduced by NXF1-p15 siRNA, demonstrating that both HBc and pgRNA use the NXF1-p15 pathway.","method":"Co-immunoprecipitation; siRNA knockdown; RT-qPCR; Northern blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple TREX components plus siRNA knockdown with quantitative RNA readouts, single lab","pmids":["25360769"],"is_preprint":false},{"year":2019,"finding":"Mip6 (a four-RRM RNA-binding protein in yeast) directly interacts with the UBA domain of Mex67 through a loop containing tryptophan 442; Mip6 shuttles between nucleus and cytoplasm in a Mex67-dependent manner and its deletion affects export and expression levels of Msn2/4-regulated stress-response mRNAs.","method":"Structural characterization; FRET-based binding assays; PAR-CLIP; genetic knockout analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction structurally defined, PAR-CLIP identifies RNA substrates, functional export defect shown, single lab","pmids":["31680439"],"is_preprint":false},{"year":2017,"finding":"NXF1 interacts with IRF5 and is identified as a regulator of TLR7-dependent IRF5 transcriptional signaling; TLR7 stimulation enhances IRF5-NXF1 protein complex formation, and gain/loss-of-function experiments confirm NXF1 selectively regulates TLR7-driven IRF5 transcriptional activity.","method":"Affinity purification-mass spectrometry; RNAi screen; co-immunoprecipitation; gain/loss-of-function reporter assays","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction identified by AP-MS and co-IP, functional role shown by knockdown, mechanism not fully resolved, single lab","pmids":["28578407"],"is_preprint":false},{"year":2022,"finding":"NXF1 is required for export of Ebola virus (EBOV) mRNAs from cytoplasmic viral inclusion bodies (IBs). RNA binding by both NXF1 and EBOV NP is necessary for NXF1 export from IBs; NP and NXF1 interact at two separate sites (one involving the NP RNA-binding cleft), these interactions are RNA-independent. NXF1 is also required for mRNA expression from other IB-replicating viruses (Lloviu, Junín).","method":"siRNA knockdown; complementation assays; immunofluorescence; domain-mapping co-immunoprecipitation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection with domain mapping, multiple viral systems tested, single lab","pmids":["36040180"],"is_preprint":false},{"year":2020,"finding":"The DEAD-box helicase Dbp5 associates in close proximity with Mex67 and Nab2 in a cellular complex at the cytoplasmic face of the NPC; anchoring Dbp5 to Nup159 is sufficient for cell viability, supporting a model where Dbp5 remodels mRNPs by locally releasing Mex67 and Nab2 at the NPC.","method":"Proximity ligation assay; genetic NUP fusion rescue experiments; co-immunoprecipitation","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity interaction and genetic rescue shown, single lab","pmids":["33002012"],"is_preprint":false},{"year":2007,"finding":"In vivo BiFC analysis shows Y14 and NXF1 form a complex that accumulates preferentially within and around nuclear speckles (SC35 domains); about half of these complexes are immobile in vivo and are depleted by ATP administration, suggesting an ATP-dependent nuclear retention mechanism for a fraction of mRNAs.","method":"Bimolecular fluorescence complementation (BiFC); FRAP; FLIP; co-immunoprecipitation; ATP depletion assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell BiFC with FRAP/FLIP, multiple orthogonal methods, single lab","pmids":["16431928"],"is_preprint":false},{"year":2024,"finding":"NS1-BP competes with viral NS1 protein for NXF1 binding during influenza A infection, allowing NXF1 recruitment to influenza M segment mRNAs after splicing. NXF1 then binds GANP (a TREX-2 component), and the NS1/NS1-BP–GANP–NXF1 complex dissociates at the NPC to allow M1 and M2 mRNA export.","method":"Co-immunoprecipitation; biochemical competition assays; subcellular mRNA localization; siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competition for NXF1 binding shown biochemically, functional mRNA export consequence demonstrated, single lab","pmids":["39384042"],"is_preprint":false},{"year":2025,"finding":"NXF1 interacts with CDK12 kinase; NXF1 does not phosphorylate CDK12, but rather stabilizes CDK12 protein. CDK12 kinase activity recruits the EJC and THO complexes into a CDK12-NXF1 axis, linking mRNA transcription and transport.","method":"Co-immunoprecipitation; protein stability assays; kinase assays; complex interaction studies","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and stability assay, mechanism partially characterized, single lab","pmids":["39270556"],"is_preprint":false},{"year":2025,"finding":"NXF1 inhibits ECa cell proliferation and invasion; mechanistically, NXF1 interferes with SRSF3 binding to exon 3 of SP4 pre-mRNA, promoting the short (non-oncogenic) SP4 isoform over the long (oncogenic) isoform through an SRSF3-mediated alternative splicing mechanism.","method":"Mouse tumor models; molecular biology assays (co-IP, splicing assays); in vitro functional assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism placed in a splicing pathway with in vitro and in vivo evidence, single lab","pmids":["40792019"],"is_preprint":false},{"year":2025,"finding":"The HuD linker region mediates direct interaction with TAP/NXF1; this TAP/NXF1-binding domain is functionally separable from cytoplasmic localization and is required for stimulation of cap-dependent translation and neurite outgrowth, establishing a mechanistic link between the RNA export factor NXF1 and ELAV-mediated translational control.","method":"Deletion mutant analysis; co-immunoprecipitation; translation assays; neurite outgrowth assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapped by deletion mutagenesis, functional consequences tested in multiple assays, single lab","pmids":["41110461"],"is_preprint":false}],"current_model":"NXF1 (TAP/Mex67) is the principal mRNA nuclear export receptor with a modular four-domain architecture (RRM, LRR, NTF2-like, UBA): it is imported into the nucleus via redundant karyopherin pathways, maintained in an autoinhibited conformation until TREX subunits (Aly/Thoc5) drive it open to enable mRNA binding, recruited to mRNAs by diverse adaptors including SR proteins (especially SRSF3/SRSF7), REF/ALY, RBM15, U2AF35, and neuron-specific HuD, and then transports mRNP cargo through the NPC by engaging FG-nucleoporins via its UBA and NTF2-like domains; NXF1 is released from cargo on the cytoplasmic face of the NPC in a Dbp5 helicase-dependent manner, and beyond mRNA it also participates in export of ribosomal subunits and tRNAs; its UBA domain additionally couples export to transcription by interacting with ubiquitylated THO/TREX components, and NXF1 further influences alternative splicing fidelity, alternative polyadenylation, and RNA Pol II dynamics at gene 3' ends."},"narrative":{"mechanistic_narrative":"NXF1 (TAP/Mex67) is the principal nuclear export receptor for the bulk of polyadenylated mRNA, operating as a heterodimer with p15/NXT1/Mtr2 to ferry mRNP cargo through the nuclear pore complex [PMID:11073998, PMID:11780633, PMID:11780634]. Its modular architecture — an RNP-type RNA-binding domain, leucine-rich repeats, an NTF2-like domain that heterodimerizes with p15, and a C-terminal UBA-like domain — couples RNA recognition to translocation: the UBA four-helix bundle and the p15-bound NTF2-like scaffold each provide synergistic FG-nucleoporin binding sites that drive directional export [PMID:11073998, PMID:11875519, PMID:12101235]. Structural work shows NXF1-NXT1 forms a domain-swapped, two-fold symmetric RNA-binding platform that recognizes structured export elements such as the CTE, with the NTF2-like domain itself extending the RNA-binding surface [PMID:25628361, PMID:25618852]. NXF1 is autoinhibited until the TREX subunits Aly and Thoc5 contact it and drive an open conformation that licenses mRNA binding [PMID:22893130], and it is loaded onto cargo by a diverse set of adaptors including U2AF35, SR proteins (most potently SRSF3 and SRSF7), RBM15/RBM15B, and the neuron-specific HuD, several of which couple splicing and polyadenylation to export-factor recruitment [PMID:11724776, PMID:26944680, PMID:17001072, PMID:19586903, PMID:15358174, PMID:41110461]. Cargo selection is sequence-biased: NXF1 preferentially exports single-exon or A/U-rich, long-exon transcripts and cooperates with the cleavage factor CFI-68 to export long 3'-UTR isoforms, also influencing alternative polyadenylation and Pol II dynamics at gene 3' ends [PMID:30819645, PMID:32504555]. Recruitment to active genes is reinforced cotranscriptionally through the UBA domain, which binds polyubiquitin and the ubiquitylated THO component Hpr1, with an FXFG/Hpr1 binding switch on the UBA controlling the handover between transcription and translocation [PMID:17056718, PMID:17475778, PMID:19401465]. At the cytoplasmic face of the NPC, NXF1 mediates terminal mRNP release in a Dbp5 helicase-dependent manner [PMID:31375530, PMID:33002012]. Beyond mRNA, the Mex67-Mtr2 dimer exports 60S ribosomal subunits and primary tRNAs through dedicated surfaces of its NTF2-like scaffold [PMID:17434126, PMID:22956913, PMID:29212662]. A natural Nxf1 allele acts as a quantitative genetic modifier of retrotransposon-induced splicing defects, an activity recreated by a single UBA-region substitution, linking the export receptor to pre-mRNA processing fidelity [PMID:14517553, PMID:25835743]. NXF1 is also exploited by numerous viruses — including HSV-1 ICP27, EBV EB2, MLV, HBV, influenza, and Ebola — as the export route for their transcripts [PMID:15767397, PMID:19019956, PMID:19369354, PMID:19793817, PMID:24478440, PMID:25360769, PMID:39384042, PMID:36040180].","teleology":[{"year":2000,"claim":"Established the domain logic of NXF1 — how a single receptor can both grip RNA and engage the pore — by dissecting its modular architecture into RNA-binding, LRR, p15-dimerizing NTF2-like, and nucleoporin-binding UBA modules.","evidence":"Domain dissection with in vitro binding and functional export assays","pmids":["11073998"],"confidence":"High","gaps":["Did not resolve the structural basis of FG-nucleoporin contact","Adaptor-mediated cargo loading not yet mapped"]},{"year":2001,"claim":"Demonstrated genetically that NXF1/p15 is the bulk mRNA export pathway in metazoa, distinguishing it from paralogs, by showing depletion blocks export of spliced and intronless poly(A)+ RNA while NXF2-4 loss does not.","evidence":"RNAi depletion in Drosophila S2 cells with poly(A)+ FISH","pmids":["11780633","11780634"],"confidence":"High","gaps":["Did not identify which adaptors load bulk mRNA onto NXF1","Substrate sequence preferences unresolved"]},{"year":2001,"claim":"Identified the first direct splicing-to-export adaptor link by showing U2AF35 binds a distinct TAP region and helps add TAP to spliced mRNPs.","evidence":"Yeast two-hybrid, in vitro binding, co-IP, Xenopus oocyte export assays","pmids":["11724776"],"confidence":"Medium","gaps":["Single lab","Relative contribution versus REF/ALY adaptors not quantified"]},{"year":2002,"claim":"Defined the structural and functional basis of NPC engagement, showing the UBA four-helix bundle and the p15-NTF2-like scaffold provide two synergistic FG-nucleoporin sites sufficient for directional export.","evidence":"NMR structure, mutagenesis (F617A), Xenopus oocyte export assays","pmids":["11875519","12101235"],"confidence":"High","gaps":["Did not identify which specific nucleoporins are physiological docking sites in vivo"]},{"year":2003,"claim":"Linked NXF1 to pre-mRNA processing fidelity in vivo by identifying a natural Nxf1 allele that suppresses retrovirus-insertion-induced splicing defects.","evidence":"Positional complementation cloning and congenic mouse genetics with RNA analysis","pmids":["14517553"],"confidence":"High","gaps":["Causal residue not yet pinpointed","Mechanism linking export receptor to splicing outcome unresolved"]},{"year":2004,"claim":"Identified RanBP2/Nup358 as a specific physiological NPC docking site for NXF1-p15, distinguishing it from Nup214 by reciprocal depletion phenotypes.","evidence":"RNAi in Drosophila cells with immunofluorescence and FISH","pmids":["14729961"],"confidence":"High","gaps":["Does not establish order of nucleoporin contacts during translocation"]},{"year":2006,"claim":"Revealed cotranscriptional recruitment via the UBA domain, which binds polyubiquitin and protects the ubiquitylated THO component Hpr1, tying export-machinery loading to transcription.","evidence":"ChIP, in vitro binding, ubiquitin interaction assays, co-IP in yeast","pmids":["17056718"],"confidence":"High","gaps":["Structural basis of the ubiquitin/Hpr1 selectivity not yet resolved at this stage"]},{"year":2006,"claim":"Expanded the adaptor repertoire to cell-type-specific and element-specific routes by identifying neuronal HuD and RBM15 as direct NXF1 adaptors for AU-rich and RTE-containing mRNAs.","evidence":"In vitro binding, ternary complex assays, yeast two-hybrid, tethering and siRNA export readouts","pmids":["15358174","17001072"],"confidence":"Medium","gaps":["Single-lab interactions","Physiological mRNA targets in neurons not transcriptome-mapped"]},{"year":2007,"claim":"Resolved the UBA domain as a molecular switch and showed FXFG-nucleoporin and Hpr1 bind overlapping UBA sites, providing a structural logic for handing cargo from transcription to translocation.","evidence":"NMR structures of UBA alone and with FXFG peptide, mutagenesis, FRET, ChIP","pmids":["17475778","19401465"],"confidence":"High","gaps":["Temporal sequence of switching in vivo not directly visualized"]},{"year":2007,"claim":"Established a separate Mex67-Mtr2 function in 60S ribosomal subunit export via a loop-extended electrostatic NTF2-like surface that also contacts the Nup84 complex, defining a distinct cargo channel.","evidence":"In vitro reconstitution, mutagenesis, yeast genetics, crosslinking, competition assays","pmids":["17434126","22956913","18046452"],"confidence":"High","gaps":["This surface is absent in human TAP-p15, so the human ribosome-export route is unaddressed"]},{"year":2010,"claim":"Explained the mechanism of cargo handover, showing arginine methylation lowers REF/ALY RNA affinity to allow TAP to strip RNA from the adaptor during loading.","evidence":"MS methylation mapping, in vitro and in vivo RNA-binding assays, mutagenesis","pmids":["20129943"],"confidence":"High","gaps":["Methyltransferase responsible and regulation of the modification not defined here"]},{"year":2011,"claim":"Defined how NXF1 itself gets into the nucleus, mapping two cooperative NLS epitopes engaged by redundant karyopherins required for export function.","evidence":"Biochemical karyopherin binding, mutagenesis, localization and export assays","pmids":["21965294"],"confidence":"High","gaps":["Relative in vivo flux through each karyopherin pathway not quantified"]},{"year":2011,"claim":"Identified a nuclear quality-control brake, showing Tpr selectively restricts export of intron-retaining mRNAs through the NXF1 pathway without affecting CRM1 cargo.","evidence":"RNAi knockdown with pathway-specific CTE versus RRE reporters","pmids":["21613532"],"confidence":"Medium","gaps":["Single lab","Direct Tpr-NXF1 contact and discrimination mechanism unresolved"]},{"year":2012,"claim":"Resolved how RNA binding is gated, showing NXF1 is autoinhibited until Aly and Thoc5 drive it open to expose its RNA-binding domain.","evidence":"Co-IP, RNA-binding assays, dual RNAi with export readout","pmids":["22893130"],"confidence":"High","gaps":["Structure of the open versus closed state in human NXF1 not solved here"]},{"year":2015,"claim":"Provided high-resolution structural frameworks for the RNA-binding platform, showing the domain-swapped NXF1-NXT1 dimer and the NTF2-like contribution to RNA binding.","evidence":"X-ray crystallography of human NXF1-NXT1 and yeast Mex67-Mtr2, SAXS, RNA-binding assays","pmids":["25628361","25618852"],"confidence":"High","gaps":["Full-length receptor with mobile RRM/UBA domains on cargo not captured"]},{"year":2015,"claim":"Pinpointed the genetic modifier to a single UBA-region residue (E610G), causally connecting NXF1 to alternative-splicing outcomes at retrotransposon insertions.","evidence":"CRISPR/Cas9 editing in co-isogenic mice with transcriptome-wide splicing arrays","pmids":["25835743"],"confidence":"High","gaps":["Biochemical effect of E610G on UBA-ubiquitin/nucleoporin binding not directly measured"]},{"year":2015,"claim":"Identified TREX-2 as an mRNP concentrator at the pore entrance, showing Sac3 phenylalanine motifs engage the Mex67 NTF2-like domain like FG-nucleoporins.","evidence":"Crystal structure, in vitro reconstitution, yeast genetics and export assays","pmids":["26051714"],"confidence":"High","gaps":["How TREX-2 hands cargo to FG-nucleoporins not directly observed"]},{"year":2016,"claim":"Defined SR proteins as principal, sequence-specific export adaptors, with SRSF3/SRSF7 co-binding mRNA adjacent to NXF1 and coupling alternative splicing and polyadenylation to export.","evidence":"iCLIP co-binding analysis, siRNA knockdown, RNA-seq","pmids":["26944680"],"confidence":"High","gaps":["Direct SRSF-NXF1 contact interface not structurally defined"]},{"year":2016,"claim":"Revealed an autoregulatory neuronal isoform, sNxf1, an intron-retaining CTE-exported variant that heterodimerizes with full-length NXF1 and can substitute for NXT1 to promote translation of CTE mRNAs.","evidence":"Brain immunofluorescence, fractionation, co-IP, reporter and polyribosome assays","pmids":["27708137"],"confidence":"Medium","gaps":["Single lab","Physiological neuronal mRNA targets and in vivo function not established"]},{"year":2017,"claim":"Extended Mex67-Mtr2 function to tRNA export, showing it cofunctions with Los1 and can substitute for it in primary tRNA nuclear export.","evidence":"Genetic inactivation, tRNA FISH, in vivo co-IP, overexpression rescue in yeast","pmids":["29212662"],"confidence":"High","gaps":["Whether human TAP-p15 exports tRNAs is not addressed"]},{"year":2019,"claim":"Localized the essential export step spatially and temporally, showing Mex67/NXF1 acts at the NPC and is required for terminal mRNP release on the cytoplasmic face in a Dbp5-dependent manner rather than for initial docking.","evidence":"FRAP/single-molecule tracking, nucleoporin-fusion rescue, superresolution microscopy, FLIM-FRET, proximity ligation","pmids":["31753862","31375530","33002012"],"confidence":"High","gaps":["Molecular trigger that times Dbp5-driven release relative to translocation not fully resolved"]},{"year":2019,"claim":"Connected NXF1 to 3'-end processing and Pol II dynamics, showing it promotes distal polyA site usage and cooperates with CFI-68 to export long 3'-UTR transcripts.","evidence":"siRNA knockdown, RNA-seq, Pol II ChIP-seq, 3'-end sequencing, co-IP","pmids":["30819645"],"confidence":"High","gaps":["Direct mechanism by which export coupling feeds back on Pol II termination unresolved"]},{"year":2020,"claim":"Defined cargo selection rules, showing NXF1 preferentially exports single/few-exon, long, A/U-rich transcripts whereas TREX favors spliced G/C-rich mRNAs, with short sufficient sequence elements identified.","evidence":"Quantitative RNA fractionation after depletion and massively parallel reporter assays","pmids":["32504555"],"confidence":"High","gaps":["Adaptor(s) reading the A/U-rich determinants not fully assigned"]},{"year":2025,"claim":"Placed NXF1 directly in alternative-splicing-driven oncogenic control, showing it interferes with SRSF3 binding to SP4 pre-mRNA to favor the non-oncogenic isoform and suppress carcinoma proliferation.","evidence":"Mouse tumor models, co-IP and splicing assays, in vitro functional assays","pmids":["40792019"],"confidence":"Medium","gaps":["Single lab","Generality of splicing regulation beyond SP4 not established"]},{"year":null,"claim":"How NXF1 integrates its diverse roles — bulk export, isoform-specific selection, ribosome/tRNA export, cotranscriptional ubiquitin sensing, and reported signaling roles — into a unified regulatory program remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["The IRF5/TLR7 and CDK12-stabilization roles rest on single low-confidence studies","No structure of full-length receptor engaging cargo at the NPC","Adaptor hierarchy across cell types not quantitatively resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8,10,24]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,18,20]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,9,12,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,17]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,17,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,18]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[38]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,8,20]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,18,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,19]}],"complexes":["NXF1-NXT1/p15 (Mex67-Mtr2) heterodimer","TREX","TREX-2"],"partners":["NXT1","ALYREF","THOC5","SRSF3","SRSF7","U2AF1","RBM15","DDX19/DBP5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBU9","full_name":"Nuclear RNA export factor 1","aliases":["Tip-associated protein","Tip-associating protein","mRNA export factor TAP"],"length_aa":619,"mass_kda":70.2,"function":"Involved in the nuclear export of mRNA species bearing retroviral constitutive transport elements (CTE) and in the export of mRNA from the nucleus to the cytoplasm (TAP/NFX1 pathway) (PubMed:10924507). The NXF1-NXT1 heterodimer is involved in the export of HSP70 mRNA in conjunction with ALYREF/THOC4 and THOC5 components of the TREX complex (PubMed:18364396, PubMed:19165146, PubMed:9660949). ALYREF/THOC4-bound mRNA is thought to be transferred to the NXF1-NXT1 heterodimer for export (PubMed:18364396, PubMed:19165146, PubMed:9660949). Also involved in nuclear export of m6A-containing mRNAs: interaction between SRSF3 and YTHDC1 facilitates m6A-containing mRNA-binding to both SRSF3 and NXF1, promoting mRNA nuclear export (PubMed:28984244)","subcellular_location":"Nucleus; Nucleus, nucleoplasm; Nucleus speckle; Nucleus, nuclear pore complex; Nucleus envelope; Cytoplasm; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q9UBU9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NXF1","classification":"Common Essential","n_dependent_lines":1194,"n_total_lines":1208,"dependency_fraction":0.9884105960264901},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000162231","cell_line_id":"CID001566","localizations":[{"compartment":"nuclear_membrane","grade":3},{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"NFYA","stoichiometry":10.0},{"gene":"PES1","stoichiometry":10.0},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"EEF1A1;EEF1A1P5","stoichiometry":0.2},{"gene":"NXT2","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001566","total_profiled":1310},"omim":[{"mim_id":"621181","title":"NF-KAPPA-B-INTERACTING LONG NONCODING RNA; NKILA","url":"https://www.omim.org/entry/621181"},{"mim_id":"620833","title":"RNA-BINDING MOTIF PROTEIN 33; RBM33","url":"https://www.omim.org/entry/620833"},{"mim_id":"619906","title":"DExD-BOX HELICASE 39A; DDX39A","url":"https://www.omim.org/entry/619906"},{"mim_id":"618640","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 3; ZC3H3","url":"https://www.omim.org/entry/618640"},{"mim_id":"617037","title":"NONCODING RNA ACTIVATED BY DNA DAMAGE; NORAD","url":"https://www.omim.org/entry/617037"}],"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/NXF1"},"hgnc":{"alias_symbol":["TAP","Mex67","DKFZp667O0311"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBU9","domains":[{"cath_id":"3.30.70.330","chopping":"119-192","consensus_level":"high","plddt":90.443,"start":119,"end":192},{"cath_id":"3.80.10.10","chopping":"205-354","consensus_level":"high","plddt":94.3693,"start":205,"end":354},{"cath_id":"3.10.450.50","chopping":"380-545","consensus_level":"high","plddt":95.1878,"start":380,"end":545},{"cath_id":"1.10.8.10","chopping":"564-616","consensus_level":"high","plddt":74.5919,"start":564,"end":616}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBU9-F1-predicted_aligned_error_v6.png","plddt_mean":79.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NXF1","jax_strain_url":"https://www.jax.org/strain/search?query=NXF1"},"sequence":{"accession":"Q9UBU9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBU9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBU9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBU9"}},"corpus_meta":[{"pmid":"26944680","id":"PMC_26944680","title":"SR 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comprising an RNP-type RNA-binding domain, four leucine-rich repeats (LRR), an NTF2-like domain that mediates heterodimerization with p15/NXT1, and a UBA-like domain that mediates interaction with FG-nucleoporins at the nuclear pore complex.\",\n      \"method\": \"Domain analysis, in vitro binding assays, functional export assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain dissection with multiple binding assays and functional validation, replicated across multiple studies\",\n      \"pmids\": [\"11073998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C-terminal UBA-like domain of NXF1/TAP has a four-helix bundle structure and mediates FG-nucleoporin binding; mutation F617A suppresses this interaction. The NTF2-like scaffold (heterodimerized with p15) provides a second nucleoporin-binding site, and both sites act synergistically; two copies of either domain alone are sufficient for directional mRNA export independent of p15.\",\n      \"method\": \"NMR structure determination; mutagenesis; Xenopus oocyte export assays\",\n      \"journal\": \"Nature structural biology / Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis in one study (PMID:11875519) and functional dissection confirmed in PMID:12101235\",\n      \"pmids\": [\"11875519\", \"12101235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila NXF1 (small bristles/sbr) and p15 are essential for nuclear export of the bulk of polyadenylated mRNAs (heat-shock and non-heat-shock, spliced and intronless) in Drosophila cells; depletion of NXF2–NXF4 has no equivalent phenotype.\",\n      \"method\": \"RNAi depletion in Drosophila S2 cells; fluorescence in situ hybridization (FISH) for poly(A)+ RNA\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with specific nuclear accumulation phenotype, replicated in two independent Drosophila studies (PMID:11780633, PMID:11780634)\",\n      \"pmids\": [\"11780633\", \"11780634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The nucleoporin RanBP2/Nup358 (cytoplasmic filaments of the NPC) provides a major binding site for NXF1-p15 dimers; depletion of RanBP2 causes NXF1 to redistribute to the cytoplasm and blocks mRNA export, whereas depletion of CAN/Nup214 blocks export without displacing NXF1, demonstrating specificity of the RanBP2–NXF1 interaction.\",\n      \"method\": \"RNAi depletion in Drosophila cells; immunofluorescence; FISH\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal RNAi comparisons with specific localization and export phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"14729961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NXF1/TAP is recruited to spliced mRNPs via a direct interaction with U2AF35 (small subunit of splicing factor U2AF); a distinct region of TAP mediates this interaction, which is evolutionarily conserved across metazoa and facilitates TAP's addition to mRNA substrates.\",\n      \"method\": \"Yeast two-hybrid; in vitro binding with recombinant proteins; co-immunoprecipitation; Xenopus oocyte export assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed in vitro and in cell context, single lab, two orthogonal methods\",\n      \"pmids\": [\"11724776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The UBA domain of yeast Mex67 (NXF1 ortholog) directly interacts with polyubiquitin chains and with Hpr1 (a THO/TREX component that is regulated by ubiquitylation in a transcription-dependent manner), transiently protecting Hpr1 from proteasomal degradation and thereby recruiting the mRNA export machinery to transcribing genes.\",\n      \"method\": \"Chromatin immunoprecipitation; in vitro binding; mutagenesis; co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, in vitro binding, ubiquitin interaction assays) in a single focused study\",\n      \"pmids\": [\"17056718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The yeast Mex67-Mtr2 heterodimer mediates nuclear export of 60S ribosomal subunits via a distinct loop-extended electrostatic surface on its NTF2-like scaffold that binds pre-60S particles and 5S rRNA; this surface is absent from human TAP-p15 and is separate from the mRNA export interface.\",\n      \"method\": \"Biochemical interaction assays; mutagenesis; yeast genetics; ribosome export assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution plus mutagenesis plus genetic epistasis, replicated in independent yeast studies\",\n      \"pmids\": [\"17434126\", \"22956913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mex67-Mtr2 interacts with the Nup84 complex (a structural NPC module lacking FG repeats) through the same loop surface that recruits pre-60S particles; Nup85 is the direct contact subunit. This interaction is essential for mRNA export.\",\n      \"method\": \"Chemical crosslinking; in vitro competition assays; yeast genetic suppressor analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — crosslinking identified contact subunit, competition assay confirmed overlap, genetic suppression, single lab\",\n      \"pmids\": [\"18046452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NXF1 uses an intramolecular interaction to autoinhibit its RNA-binding activity. The TREX subunits Aly and Thoc5 contact NXF1 and drive it into an open conformation that exposes its RNA-binding domain, licensing mRNA binding. Combined knockdown of Aly and Thoc5 markedly reduces NXF1-mRNA association and causes severe mRNA export block.\",\n      \"method\": \"Co-immunoprecipitation; RNA-binding assays; RNAi knockdown with mRNA export readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conformational activation mechanism supported by multiple biochemical and cellular assays, clear mechanistic model\",\n      \"pmids\": [\"22893130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SR proteins (SRSF1-7) act as NXF1 export adaptors that bind mRNA at sites adjacent to NXF1-binding sites (co-binding). SRSF3 and SRSF7 each promote NXF1 recruitment to mRNA and couple alternative splicing and polyadenylation to NXF1-mediated export; SRSF3 is the most potent adaptor and confers sequence specificity to NXF1 binding in last exons.\",\n      \"method\": \"iCLIP (individual-nucleotide-resolution UV cross-linking and immunoprecipitation); siRNA knockdown; RNAseq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptome-wide iCLIP with quantitative co-binding analysis plus functional export assays, multiple SR proteins tested in parallel\",\n      \"pmids\": [\"26944680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure (3.4 Å) of human NXF1 (RRM-LRR-NTF2-like domains) in complex with NXT1 reveals a domain-swapped dimer in which linkers between LRR and NTF2-like domains interact with NXT1, forming a 2-fold symmetric RNA-binding platform that facilitates recognition of the CTE RNA stem-loop and promotes its nuclear export.\",\n      \"method\": \"X-ray crystallography; biochemical binding assays; cell-based export assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with complementary biochemical and cellular validation\",\n      \"pmids\": [\"25628361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NXF1/TAP directly interacts with the neuronal RNA-binding protein HuD (but not the ubiquitous HuR); HuD forms a ternary complex with TAP and RNA, suggesting HuD acts as a neuron-specific adaptor for NXF1-mediated export of AU-rich element-containing mRNAs.\",\n      \"method\": \"In vitro binding with recombinant proteins; ternary complex formation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding demonstrated, ternary complex shown, single lab\",\n      \"pmids\": [\"15358174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBM15 (OTT1) directly binds the RNA transport element RTE and interacts directly with NXF1 via its C-terminal region, functioning as a novel export adaptor that links RTE-containing mRNAs to the NXF1 export pathway.\",\n      \"method\": \"In vitro RNA binding; yeast two-hybrid; co-immunoprecipitation; tethering assay; siRNA knockdown with export readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding and protein-protein interaction demonstrated in vitro; functional tethering assay confirms export activity, single lab\",\n      \"pmids\": [\"17001072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM15B/OTT3, like its paralog RBM15, directly interacts with NXF1 and Aly/REF via its C-terminal region, associates with the splicing factor compartment and nuclear envelope, and has post-transcriptional regulatory activity, functioning as an NXF1 cofactor.\",\n      \"method\": \"Co-immunoprecipitation; subcellular localization; mutational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction mapped by mutagenesis and co-IP, functional context provided, single lab\",\n      \"pmids\": [\"19586903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Arginine methylation of REF/ALY reduces its RNA-binding affinity without affecting its TAP/NXF1 interaction; this reduced RNA binding is required for efficient displacement of RNA from REF by TAP during the handover of mRNA to NXF1 for export.\",\n      \"method\": \"Mass spectrometry methylation mapping; in vitro binding assays; in vivo RNA-binding assays; mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — PTM sites mapped by MS, mechanistic handover tested by multiple orthogonal biochemical and cellular methods\",\n      \"pmids\": [\"20129943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The nuclear protein Tpr restricts nuclear export of intron-retaining mRNAs that traffic through the NXF1/Nxt1 pathway; Tpr knockdown increases export and translation from a CTE-containing retained-intron reporter but has no effect on CRM1-pathway (Rev/RRE) export or completely spliced mRNA export.\",\n      \"method\": \"RNAi knockdown; reporter mRNA export/expression assays (CTE vs. RRE reporters); pathway-specific readouts\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using two pathway-specific reporters, clean knockdown, single lab\",\n      \"pmids\": [\"21613532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NXF1 is imported into the nucleus via redundant karyopherin pathways (importin β, karyopherin β2/transportin, importin 4, importin 11, importin α). Two NLS epitopes in NXF1's N-terminal tail (an N-terminal basic segment and an R-X2-5-P-Y motif) provide the majority of binding energy; mutation of both NLS epitopes mislocalizes NXF1 to the cytoplasm and impairs mRNA export function.\",\n      \"method\": \"Biochemical binding assays; mutagenesis; cellular localization studies; functional export assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — five karyopherins tested biochemically, NLS epitopes mapped by mutagenesis, functional consequence demonstrated\",\n      \"pmids\": [\"21965294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In yeast, Mex67 localizes constitutively to the NPC independently of mRNA, occupying FG-repeat binding sites; its essential export function is spatially restricted to the NPC, as a Mex67-Nup116 fusion that anchors Mex67 at the NPC rescues mex67Δ. Mex67 has little interaction with mRNA in the nucleus and receives export substrates at the NPC channel.\",\n      \"method\": \"Quantitative live-cell fluorescence microscopy (FRAP, single-molecule tracking); genetic rescue with nucleoporin fusion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative live imaging plus genetic rescue experiment define spatial restriction of function\",\n      \"pmids\": [\"31753862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NXF1 is required for mRNA release on the cytoplasmic side of the NPC but not for initial mRNP docking to the NPC. NXF1 occupies cytoplasmic-side positions within the NPC (superresolution microscopy), and its NPC localization is RNA-independent. Dbp5 helicase activity is required for mRNP release at the cytoplasmic face, a mechanism conserved between yeast and humans.\",\n      \"method\": \"Live-cell mRNA export block assays; superresolution microscopy; FLIM-FRET within single NPCs\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — superresolution localization combined with FLIM-FRET protein-protein interaction measurements within single NPCs\",\n      \"pmids\": [\"31375530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NXF1 downregulation causes RNA Pol II accumulation at the 3' end of genes; NXF1 promotes usage of distal polyadenylation sites, generating long 3' UTR isoforms. NXF1 cooperates with the cleavage factor CFI-68 to facilitate nuclear export of long 3' UTR transcripts containing UGUA motifs.\",\n      \"method\": \"siRNA knockdown; RNA-seq; Pol II ChIP-seq; 3' end sequencing (APA profiling); co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide transcriptomic and Pol II ChIP approaches combined with biochemical co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"30819645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NXF1 is preferentially required for nuclear export of single-exon or few-exon transcripts with long exons or high A/U content, while TREX complex components preferentially facilitate export of spliced G/C-rich transcripts. Short sequence elements sufficient to confer NXF1-dependence were identified by massively parallel reporter assays.\",\n      \"method\": \"Quantitative RNA fractionation after siRNA depletion; massively parallel reporter assays; transcriptome-wide RNA localization profiling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptome-wide quantitative localization profiling combined with reporter assays, multiple export factors compared\",\n      \"pmids\": [\"32504555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mex67-Mtr2 (TAP-p15) cofunctions with Los1 (Exportin-t) in primary tRNA nuclear export in yeast; inactivation of Mex67 or Mtr2 causes nuclear accumulation of end-matured unspliced tRNAs, and Mex67 co-immunoprecipitates with tRNAs in vivo. Mex67-Mtr2 overexpression can substitute for Los1.\",\n      \"method\": \"Genetic inactivation; FISH for tRNA localization; in vivo co-immunoprecipitation; overexpression rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and biochemical approaches, genetic complementation, direct RNA-protein association shown\",\n      \"pmids\": [\"29212662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The UBA domain of Mex67 has a classical three-helix UBA fold plus a fourth helix (H4) that acts as a molecular switch: H4 coordinates interaction with ubiquitin-bound Hpr1, selects for polyubiquitin, and prevents binding to non-specific substrates. Deletion or mutation of H4 strengthens ubiquitin binding but decreases Hpr1 affinity and reduces cotranscriptional Mex67 recruitment and mRNA export.\",\n      \"method\": \"NMR structure; mutagenesis; fluorescence-based binding assays; chromatin immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus mutagenesis plus ChIP, multiple orthogonal functional assays\",\n      \"pmids\": [\"17475778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NMR solution structure of the Mex67 UBA domain complexed with an FXFG nucleoporin peptide shows that Hpr1 and FXFG nucleoporins bind overlapping sites on UBA-Mex67; FXFG binding prevents UBA-Mex67 from subsequently binding ubiquitin, whereas Hpr1 binding allows polyubiquitin interaction.\",\n      \"method\": \"NMR structure; FRET-based binding assays; NMR titration\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure of complex plus FRET and NMR titration, multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"19401465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure (3.3 Å) of yeast Mex67(ΔUBA):Mtr2 shows the LRR domain has a defined spatial relationship to the NTF2-like region; the NTF2-like domain of Mex67:Mtr2 contributes directly to RNA binding, extending the mRNA-binding surface. RRM and UBA domains are more mobile.\",\n      \"method\": \"X-ray crystallography; SAXS; RNA-binding assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with SAXS and in vitro RNA-binding assays\",\n      \"pmids\": [\"25618852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The TREX-2 complex (Sac3-Thp1-Sem1-Sus1-Cdc31) interacts with Mex67:Mtr2 through the Sac3 N-terminal region via phenylalanine-containing motifs that bind the Mex67 NTF2-like domain similarly to FG-nucleoporins; deletion of Sac3N causes mRNA export defects, placing TREX-2 as a concentrator of mRNPs at the NPC entrance.\",\n      \"method\": \"Crystal structure; in vitro reconstitution; yeast genetic growth and export assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus genetic functional validation\",\n      \"pmids\": [\"26051714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A natural allele of mouse Nxf1 (Nxf1^CAST from Mus musculus castaneus) suppresses intronic endogenous retrovirus insertion-induced mutations (Pitpn^vb, Eya1^BOR) by increasing correctly spliced mRNA and decreasing aberrant alternatively processed RNA, linking the mRNA export receptor to pre-mRNA processing fidelity.\",\n      \"method\": \"Positional complementation cloning; congenic mouse genetics; RNA analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic positional cloning identifies the gene; congenic allele directly suppresses multiple independent mutations\",\n      \"pmids\": [\"14517553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A single amino acid substitution E610G in Nxf1 (within the UBA domain region) is sufficient to recreate the quantitative genetic modifier activity of the Nxf1^CAST allele for IAP retrotransposon insertion-induced alternative splicing defects, as demonstrated by CRISPR/Cas9-mediated genome editing.\",\n      \"method\": \"CRISPR/Cas9 genome editing; genome-wide splicing-sensitive microarrays; gene-focused splicing assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single amino acid change introduced by CRISPR in co-isogenic background with transcriptome-wide splicing validation\",\n      \"pmids\": [\"25835743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila NXF1/sbr loss-of-function causes disruption of the meiotic spindle in females and formation of tripolar spindles during the first meiotic division; the sbr^5 lethal allele deletes 492 nucleotides removing residues within the NTF2-like domain.\",\n      \"method\": \"Genetic analysis of mutant alleles; cytological analysis of meiotic spindles; sequencing of sbr allele\",\n      \"journal\": \"Chromosome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function phenotype in meiosis linked to specific domain deletion, single lab, single method\",\n      \"pmids\": [\"19779841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An NXF1 isoform (short NXF1, sNxf1), translated from an intron-10-retaining mRNA exported via a CTE element, is highly expressed in hippocampal and neocortical neurons. sNxf1 localizes to RNA granules in neurites, forms heterodimers with full-length NXF1, and can replace NXT1 to enhance expression of CTE-containing mRNA and promote its association with polyribosomes.\",\n      \"method\": \"Immunofluorescence in rodent brain; subcellular fractionation; co-immunoprecipitation; reporter expression/polyribosome profiling assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neuronal expression confirmed, heterodimer and functional replacement shown biochemically, single lab\",\n      \"pmids\": [\"27708137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NXF1 TAP/NXF1 directly interacts with the HSV-1 protein ICP27 via the C-terminus of ICP27 (with N-terminal contribution); this interaction is required for ICP27's cytoplasmic export and for efficient nuclear export of HSV-1 viral transcripts. Aly/REF is not required for ICP27 export despite being recruited to viral transcription sites.\",\n      \"method\": \"Co-immunoprecipitation; in vitro binding; siRNA knockdown; in situ hybridization\",\n      \"journal\": \"Journal of virology / Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding shown in vitro, functional consequence confirmed by siRNA knockdown and RNA export assays, replicated across multiple HSV studies\",\n      \"pmids\": [\"15767397\", \"19019956\", \"19369354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Epstein-Barr virus protein EB2 contains a CRM1-independent nuclear export signal (NES, aa 61–146) composed of arginine-rich domains that interact directly with TAP/NXF1 and mediate mRNA export; the NES fused to a heterologous protein can export MS2-tethered mRNA.\",\n      \"method\": \"Co-immunoprecipitation; tethering export assay; mutagenesis\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped to specific domain, tethering assay demonstrates export activity, single lab\",\n      \"pmids\": [\"19793817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The gammaretrovirus MLV (murine leukemia virus) contains a cis-acting cytoplasmic accumulation element (CAE) in the pol gene that binds NXF1 directly; NXF1 depletion abolishes CAE function and causes nuclear retention or degradation of both spliced and unspliced MLV RNA transcripts.\",\n      \"method\": \"siRNA knockdown; RNA immunoprecipitation; FISH; co-immunoprecipitation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein interaction shown, functional consequences of NXF1 loss confirmed by FISH and RIP, single lab\",\n      \"pmids\": [\"24478440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HBV core protein (HBc) associates with TREX components and NXF1-p15 by co-immunoprecipitation, and interference with NXF1-p15 function causes nuclear accumulation of HBc. HBV pregenomic RNA (pgRNA) export to the cytoplasm is reduced by NXF1-p15 siRNA, demonstrating that both HBc and pgRNA use the NXF1-p15 pathway.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; RT-qPCR; Northern blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple TREX components plus siRNA knockdown with quantitative RNA readouts, single lab\",\n      \"pmids\": [\"25360769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mip6 (a four-RRM RNA-binding protein in yeast) directly interacts with the UBA domain of Mex67 through a loop containing tryptophan 442; Mip6 shuttles between nucleus and cytoplasm in a Mex67-dependent manner and its deletion affects export and expression levels of Msn2/4-regulated stress-response mRNAs.\",\n      \"method\": \"Structural characterization; FRET-based binding assays; PAR-CLIP; genetic knockout analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction structurally defined, PAR-CLIP identifies RNA substrates, functional export defect shown, single lab\",\n      \"pmids\": [\"31680439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NXF1 interacts with IRF5 and is identified as a regulator of TLR7-dependent IRF5 transcriptional signaling; TLR7 stimulation enhances IRF5-NXF1 protein complex formation, and gain/loss-of-function experiments confirm NXF1 selectively regulates TLR7-driven IRF5 transcriptional activity.\",\n      \"method\": \"Affinity purification-mass spectrometry; RNAi screen; co-immunoprecipitation; gain/loss-of-function reporter assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction identified by AP-MS and co-IP, functional role shown by knockdown, mechanism not fully resolved, single lab\",\n      \"pmids\": [\"28578407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NXF1 is required for export of Ebola virus (EBOV) mRNAs from cytoplasmic viral inclusion bodies (IBs). RNA binding by both NXF1 and EBOV NP is necessary for NXF1 export from IBs; NP and NXF1 interact at two separate sites (one involving the NP RNA-binding cleft), these interactions are RNA-independent. NXF1 is also required for mRNA expression from other IB-replicating viruses (Lloviu, Junín).\",\n      \"method\": \"siRNA knockdown; complementation assays; immunofluorescence; domain-mapping co-immunoprecipitation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection with domain mapping, multiple viral systems tested, single lab\",\n      \"pmids\": [\"36040180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The DEAD-box helicase Dbp5 associates in close proximity with Mex67 and Nab2 in a cellular complex at the cytoplasmic face of the NPC; anchoring Dbp5 to Nup159 is sufficient for cell viability, supporting a model where Dbp5 remodels mRNPs by locally releasing Mex67 and Nab2 at the NPC.\",\n      \"method\": \"Proximity ligation assay; genetic NUP fusion rescue experiments; co-immunoprecipitation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity interaction and genetic rescue shown, single lab\",\n      \"pmids\": [\"33002012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In vivo BiFC analysis shows Y14 and NXF1 form a complex that accumulates preferentially within and around nuclear speckles (SC35 domains); about half of these complexes are immobile in vivo and are depleted by ATP administration, suggesting an ATP-dependent nuclear retention mechanism for a fraction of mRNAs.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC); FRAP; FLIP; co-immunoprecipitation; ATP depletion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell BiFC with FRAP/FLIP, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16431928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NS1-BP competes with viral NS1 protein for NXF1 binding during influenza A infection, allowing NXF1 recruitment to influenza M segment mRNAs after splicing. NXF1 then binds GANP (a TREX-2 component), and the NS1/NS1-BP–GANP–NXF1 complex dissociates at the NPC to allow M1 and M2 mRNA export.\",\n      \"method\": \"Co-immunoprecipitation; biochemical competition assays; subcellular mRNA localization; siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competition for NXF1 binding shown biochemically, functional mRNA export consequence demonstrated, single lab\",\n      \"pmids\": [\"39384042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NXF1 interacts with CDK12 kinase; NXF1 does not phosphorylate CDK12, but rather stabilizes CDK12 protein. CDK12 kinase activity recruits the EJC and THO complexes into a CDK12-NXF1 axis, linking mRNA transcription and transport.\",\n      \"method\": \"Co-immunoprecipitation; protein stability assays; kinase assays; complex interaction studies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and stability assay, mechanism partially characterized, single lab\",\n      \"pmids\": [\"39270556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NXF1 inhibits ECa cell proliferation and invasion; mechanistically, NXF1 interferes with SRSF3 binding to exon 3 of SP4 pre-mRNA, promoting the short (non-oncogenic) SP4 isoform over the long (oncogenic) isoform through an SRSF3-mediated alternative splicing mechanism.\",\n      \"method\": \"Mouse tumor models; molecular biology assays (co-IP, splicing assays); in vitro functional assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism placed in a splicing pathway with in vitro and in vivo evidence, single lab\",\n      \"pmids\": [\"40792019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The HuD linker region mediates direct interaction with TAP/NXF1; this TAP/NXF1-binding domain is functionally separable from cytoplasmic localization and is required for stimulation of cap-dependent translation and neurite outgrowth, establishing a mechanistic link between the RNA export factor NXF1 and ELAV-mediated translational control.\",\n      \"method\": \"Deletion mutant analysis; co-immunoprecipitation; translation assays; neurite outgrowth assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapped by deletion mutagenesis, functional consequences tested in multiple assays, single lab\",\n      \"pmids\": [\"41110461\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NXF1 (TAP/Mex67) is the principal mRNA nuclear export receptor with a modular four-domain architecture (RRM, LRR, NTF2-like, UBA): it is imported into the nucleus via redundant karyopherin pathways, maintained in an autoinhibited conformation until TREX subunits (Aly/Thoc5) drive it open to enable mRNA binding, recruited to mRNAs by diverse adaptors including SR proteins (especially SRSF3/SRSF7), REF/ALY, RBM15, U2AF35, and neuron-specific HuD, and then transports mRNP cargo through the NPC by engaging FG-nucleoporins via its UBA and NTF2-like domains; NXF1 is released from cargo on the cytoplasmic face of the NPC in a Dbp5 helicase-dependent manner, and beyond mRNA it also participates in export of ribosomal subunits and tRNAs; its UBA domain additionally couples export to transcription by interacting with ubiquitylated THO/TREX components, and NXF1 further influences alternative splicing fidelity, alternative polyadenylation, and RNA Pol II dynamics at gene 3' ends.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NXF1 (TAP/Mex67) is the principal nuclear export receptor for the bulk of polyadenylated mRNA, operating as a heterodimer with p15/NXT1/Mtr2 to ferry mRNP cargo through the nuclear pore complex [#0, #2]. Its modular architecture — an RNP-type RNA-binding domain, leucine-rich repeats, an NTF2-like domain that heterodimerizes with p15, and a C-terminal UBA-like domain — couples RNA recognition to translocation: the UBA four-helix bundle and the p15-bound NTF2-like scaffold each provide synergistic FG-nucleoporin binding sites that drive directional export [#0, #1]. Structural work shows NXF1-NXT1 forms a domain-swapped, two-fold symmetric RNA-binding platform that recognizes structured export elements such as the CTE, with the NTF2-like domain itself extending the RNA-binding surface [#10, #24]. NXF1 is autoinhibited until the TREX subunits Aly and Thoc5 contact it and drive an open conformation that licenses mRNA binding [#8], and it is loaded onto cargo by a diverse set of adaptors including U2AF35, SR proteins (most potently SRSF3 and SRSF7), RBM15/RBM15B, and the neuron-specific HuD, several of which couple splicing and polyadenylation to export-factor recruitment [#4, #9, #12, #13, #11, #42]. Cargo selection is sequence-biased: NXF1 preferentially exports single-exon or A/U-rich, long-exon transcripts and cooperates with the cleavage factor CFI-68 to export long 3'-UTR isoforms, also influencing alternative polyadenylation and Pol II dynamics at gene 3' ends [#19, #20]. Recruitment to active genes is reinforced cotranscriptionally through the UBA domain, which binds polyubiquitin and the ubiquitylated THO component Hpr1, with an FXFG/Hpr1 binding switch on the UBA controlling the handover between transcription and translocation [#5, #22, #23]. At the cytoplasmic face of the NPC, NXF1 mediates terminal mRNP release in a Dbp5 helicase-dependent manner [#18, #37]. Beyond mRNA, the Mex67-Mtr2 dimer exports 60S ribosomal subunits and primary tRNAs through dedicated surfaces of its NTF2-like scaffold [#6, #21]. A natural Nxf1 allele acts as a quantitative genetic modifier of retrotransposon-induced splicing defects, an activity recreated by a single UBA-region substitution, linking the export receptor to pre-mRNA processing fidelity [#26, #27]. NXF1 is also exploited by numerous viruses — including HSV-1 ICP27, EBV EB2, MLV, HBV, influenza, and Ebola — as the export route for their transcripts [#30, #31, #32, #33, #39, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the domain logic of NXF1 — how a single receptor can both grip RNA and engage the pore — by dissecting its modular architecture into RNA-binding, LRR, p15-dimerizing NTF2-like, and nucleoporin-binding UBA modules.\",\n      \"evidence\": \"Domain dissection with in vitro binding and functional export assays\",\n      \"pmids\": [\"11073998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of FG-nucleoporin contact\", \"Adaptor-mediated cargo loading not yet mapped\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated genetically that NXF1/p15 is the bulk mRNA export pathway in metazoa, distinguishing it from paralogs, by showing depletion blocks export of spliced and intronless poly(A)+ RNA while NXF2-4 loss does not.\",\n      \"evidence\": \"RNAi depletion in Drosophila S2 cells with poly(A)+ FISH\",\n      \"pmids\": [\"11780633\", \"11780634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which adaptors load bulk mRNA onto NXF1\", \"Substrate sequence preferences unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the first direct splicing-to-export adaptor link by showing U2AF35 binds a distinct TAP region and helps add TAP to spliced mRNPs.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP, Xenopus oocyte export assays\",\n      \"pmids\": [\"11724776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Relative contribution versus REF/ALY adaptors not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the structural and functional basis of NPC engagement, showing the UBA four-helix bundle and the p15-NTF2-like scaffold provide two synergistic FG-nucleoporin sites sufficient for directional export.\",\n      \"evidence\": \"NMR structure, mutagenesis (F617A), Xenopus oocyte export assays\",\n      \"pmids\": [\"11875519\", \"12101235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which specific nucleoporins are physiological docking sites in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked NXF1 to pre-mRNA processing fidelity in vivo by identifying a natural Nxf1 allele that suppresses retrovirus-insertion-induced splicing defects.\",\n      \"evidence\": \"Positional complementation cloning and congenic mouse genetics with RNA analysis\",\n      \"pmids\": [\"14517553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal residue not yet pinpointed\", \"Mechanism linking export receptor to splicing outcome unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified RanBP2/Nup358 as a specific physiological NPC docking site for NXF1-p15, distinguishing it from Nup214 by reciprocal depletion phenotypes.\",\n      \"evidence\": \"RNAi in Drosophila cells with immunofluorescence and FISH\",\n      \"pmids\": [\"14729961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish order of nucleoporin contacts during translocation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed cotranscriptional recruitment via the UBA domain, which binds polyubiquitin and protects the ubiquitylated THO component Hpr1, tying export-machinery loading to transcription.\",\n      \"evidence\": \"ChIP, in vitro binding, ubiquitin interaction assays, co-IP in yeast\",\n      \"pmids\": [\"17056718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ubiquitin/Hpr1 selectivity not yet resolved at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Expanded the adaptor repertoire to cell-type-specific and element-specific routes by identifying neuronal HuD and RBM15 as direct NXF1 adaptors for AU-rich and RTE-containing mRNAs.\",\n      \"evidence\": \"In vitro binding, ternary complex assays, yeast two-hybrid, tethering and siRNA export readouts\",\n      \"pmids\": [\"15358174\", \"17001072\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interactions\", \"Physiological mRNA targets in neurons not transcriptome-mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the UBA domain as a molecular switch and showed FXFG-nucleoporin and Hpr1 bind overlapping UBA sites, providing a structural logic for handing cargo from transcription to translocation.\",\n      \"evidence\": \"NMR structures of UBA alone and with FXFG peptide, mutagenesis, FRET, ChIP\",\n      \"pmids\": [\"17475778\", \"19401465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal sequence of switching in vivo not directly visualized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established a separate Mex67-Mtr2 function in 60S ribosomal subunit export via a loop-extended electrostatic NTF2-like surface that also contacts the Nup84 complex, defining a distinct cargo channel.\",\n      \"evidence\": \"In vitro reconstitution, mutagenesis, yeast genetics, crosslinking, competition assays\",\n      \"pmids\": [\"17434126\", \"22956913\", \"18046452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"This surface is absent in human TAP-p15, so the human ribosome-export route is unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Explained the mechanism of cargo handover, showing arginine methylation lowers REF/ALY RNA affinity to allow TAP to strip RNA from the adaptor during loading.\",\n      \"evidence\": \"MS methylation mapping, in vitro and in vivo RNA-binding assays, mutagenesis\",\n      \"pmids\": [\"20129943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methyltransferase responsible and regulation of the modification not defined here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how NXF1 itself gets into the nucleus, mapping two cooperative NLS epitopes engaged by redundant karyopherins required for export function.\",\n      \"evidence\": \"Biochemical karyopherin binding, mutagenesis, localization and export assays\",\n      \"pmids\": [\"21965294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo flux through each karyopherin pathway not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a nuclear quality-control brake, showing Tpr selectively restricts export of intron-retaining mRNAs through the NXF1 pathway without affecting CRM1 cargo.\",\n      \"evidence\": \"RNAi knockdown with pathway-specific CTE versus RRE reporters\",\n      \"pmids\": [\"21613532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct Tpr-NXF1 contact and discrimination mechanism unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how RNA binding is gated, showing NXF1 is autoinhibited until Aly and Thoc5 drive it open to expose its RNA-binding domain.\",\n      \"evidence\": \"Co-IP, RNA-binding assays, dual RNAi with export readout\",\n      \"pmids\": [\"22893130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the open versus closed state in human NXF1 not solved here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided high-resolution structural frameworks for the RNA-binding platform, showing the domain-swapped NXF1-NXT1 dimer and the NTF2-like contribution to RNA binding.\",\n      \"evidence\": \"X-ray crystallography of human NXF1-NXT1 and yeast Mex67-Mtr2, SAXS, RNA-binding assays\",\n      \"pmids\": [\"25628361\", \"25618852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor with mobile RRM/UBA domains on cargo not captured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pinpointed the genetic modifier to a single UBA-region residue (E610G), causally connecting NXF1 to alternative-splicing outcomes at retrotransposon insertions.\",\n      \"evidence\": \"CRISPR/Cas9 editing in co-isogenic mice with transcriptome-wide splicing arrays\",\n      \"pmids\": [\"25835743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical effect of E610G on UBA-ubiquitin/nucleoporin binding not directly measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TREX-2 as an mRNP concentrator at the pore entrance, showing Sac3 phenylalanine motifs engage the Mex67 NTF2-like domain like FG-nucleoporins.\",\n      \"evidence\": \"Crystal structure, in vitro reconstitution, yeast genetics and export assays\",\n      \"pmids\": [\"26051714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TREX-2 hands cargo to FG-nucleoporins not directly observed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined SR proteins as principal, sequence-specific export adaptors, with SRSF3/SRSF7 co-binding mRNA adjacent to NXF1 and coupling alternative splicing and polyadenylation to export.\",\n      \"evidence\": \"iCLIP co-binding analysis, siRNA knockdown, RNA-seq\",\n      \"pmids\": [\"26944680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SRSF-NXF1 contact interface not structurally defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an autoregulatory neuronal isoform, sNxf1, an intron-retaining CTE-exported variant that heterodimerizes with full-length NXF1 and can substitute for NXT1 to promote translation of CTE mRNAs.\",\n      \"evidence\": \"Brain immunofluorescence, fractionation, co-IP, reporter and polyribosome assays\",\n      \"pmids\": [\"27708137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological neuronal mRNA targets and in vivo function not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended Mex67-Mtr2 function to tRNA export, showing it cofunctions with Los1 and can substitute for it in primary tRNA nuclear export.\",\n      \"evidence\": \"Genetic inactivation, tRNA FISH, in vivo co-IP, overexpression rescue in yeast\",\n      \"pmids\": [\"29212662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human TAP-p15 exports tRNAs is not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localized the essential export step spatially and temporally, showing Mex67/NXF1 acts at the NPC and is required for terminal mRNP release on the cytoplasmic face in a Dbp5-dependent manner rather than for initial docking.\",\n      \"evidence\": \"FRAP/single-molecule tracking, nucleoporin-fusion rescue, superresolution microscopy, FLIM-FRET, proximity ligation\",\n      \"pmids\": [\"31753862\", \"31375530\", \"33002012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger that times Dbp5-driven release relative to translocation not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected NXF1 to 3'-end processing and Pol II dynamics, showing it promotes distal polyA site usage and cooperates with CFI-68 to export long 3'-UTR transcripts.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, Pol II ChIP-seq, 3'-end sequencing, co-IP\",\n      \"pmids\": [\"30819645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism by which export coupling feeds back on Pol II termination unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined cargo selection rules, showing NXF1 preferentially exports single/few-exon, long, A/U-rich transcripts whereas TREX favors spliced G/C-rich mRNAs, with short sufficient sequence elements identified.\",\n      \"evidence\": \"Quantitative RNA fractionation after depletion and massively parallel reporter assays\",\n      \"pmids\": [\"32504555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor(s) reading the A/U-rich determinants not fully assigned\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed NXF1 directly in alternative-splicing-driven oncogenic control, showing it interferes with SRSF3 binding to SP4 pre-mRNA to favor the non-oncogenic isoform and suppress carcinoma proliferation.\",\n      \"evidence\": \"Mouse tumor models, co-IP and splicing assays, in vitro functional assays\",\n      \"pmids\": [\"40792019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality of splicing regulation beyond SP4 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NXF1 integrates its diverse roles — bulk export, isoform-specific selection, ribosome/tRNA export, cotranscriptional ubiquitin sensing, and reported signaling roles — into a unified regulatory program remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"The IRF5/TLR7 and CDK12-stabilization roles rest on single low-confidence studies\", \"No structure of full-length receptor engaging cargo at the NPC\", \"Adaptor hierarchy across cell types not quantitatively resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8, 10, 24]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 18, 20]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 9, 12, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 17]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 17, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 8, 20]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 18, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 19]}\n    ],\n    \"complexes\": [\"NXF1-NXT1/p15 (Mex67-Mtr2) heterodimer\", \"TREX\", \"TREX-2\"],\n    \"partners\": [\"NXT1\", \"ALYREF\", \"THOC5\", \"SRSF3\", \"SRSF7\", \"U2AF1\", \"RBM15\", \"DDX19/Dbp5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}