{"gene":"PQBP1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1999,"finding":"PQBP1 (PQBP-1) was identified as a nuclear protein that directly binds polyglutamine tracts (including those of Brn-2, huntingtin, and ataxin-1) with higher affinity for expanded repeats, and inhibits transcriptional activation by Brn-2. Overexpression suppresses cell growth and enhances susceptibility to stress. The protein contains a WW domain, polar amino acid repeat sequences essential for polyglutamine binding, a putative nuclear localization signal, and a C2 domain.","method":"Yeast two-hybrid screen (binding), in vitro binding assays, nuclear localization by immunofluorescence, transcription reporter assays, cell viability assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assay, transcription reporter, localization, cell survival), foundational paper replicated by subsequent work","pmids":["10332029"],"is_preprint":false},{"year":2002,"finding":"Mutant ataxin-1 (expanded polyglutamine) enhances PQBP-1 binding to the C-terminal domain of RNA polymerase II large subunit, reducing phosphorylated Pol II levels and transcription, and inducing apoptotic cell death. This interaction is positively influenced by expanded polyglutamine sequences.","method":"In vitro and in vivo binding assays, co-immunoprecipitation, transcription assays, apoptosis assays in cell lines","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, mechanistic transcription readout, multiple orthogonal methods in one study","pmids":["12062018"],"is_preprint":false},{"year":2003,"finding":"Transgenic overexpression of human PQBP-1 in mice causes a late-onset, progressive motor neuron disease-like phenotype with loss of Purkinje cells, granular cells in cerebellum, and spinal motor neurons, demonstrating that excessive PQBP-1 activity causes neuronal dysfunction.","method":"Transgenic mouse model (ubiquitous human PQBP-1 expression), behavioral analysis, histopathology","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse with defined cellular phenotype, single lab","pmids":["12651867"],"is_preprint":false},{"year":2010,"finding":"The Y65C missense mutation in the WW domain of PQBP1 (Golabi-Ito-Hall syndrome) diminishes binding of the WW domain and full-length protein to proline-rich ligands. In patient-derived lymphoblasts, the PQBP1-Y65C/WBP11 splicing factor complex was compromised and pre-mRNA splicing efficiency was substantially decreased.","method":"In vitro binding assays with recombinant proteins, co-immunoprecipitation from patient lymphoblasts, RT-PCR splicing efficiency assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding assay with mutagenesis, patient cell validation, two orthogonal methods","pmids":["20410308"],"is_preprint":false},{"year":2011,"finding":"PQBP1 localizes not only in nuclear speckles but also in a cytoplasmic pool in neurons, where it associates with RNA-binding proteins KSRP, SFPQ/PSF, DDX1, Caprin-1, and dynactin subunits p150(Glued) and p27 in RNA-dependent complexes. PQBP1 co-localizes with FMRP in neuronal RNA granules and relocalizes to stress granules upon arsenite-induced oxidative stress. The cellular distribution of PQBP1 influences stress granule assembly.","method":"Co-immunoprecipitation, immunofluorescence microscopy, RNA-dependency assay (RNase treatment), stress granule induction assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal co-IP, immunofluorescence localization with functional consequence (SG assembly), single lab","pmids":["21933836"],"is_preprint":false},{"year":2013,"finding":"PQBP1 functions as an alternative mRNA splicing effector by associating with splicing factors including the U2 snRNP component SF3B1. Loss of PQBP1 reduces SF3B1 substrate mRNA association and causes significant changes in alternative splicing patterns. In primary neurons, PQBP1 depletion reduces dendritic outgrowth. Disease-linked PQBP1 mutants are deficient in splicing factor associations and cannot complement neurite outgrowth defects.","method":"Mass spectrometry (interactome), RIP (RNA immunoprecipitation), RNA-seq (splicing analysis), PQBP1 knockdown in primary neurons, neurite outgrowth assay, complementation with disease mutants","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS interactome, RIP, RNA-seq, KD phenotype, complementation), single lab with rigorous controls","pmids":["23512658"],"is_preprint":false},{"year":2013,"finding":"PQBP1 is localized at the base of the neuronal primary cilium and its knockdown profoundly impairs ciliary morphogenesis in neurons and in the mouse cerebral cortex in vivo. PQBP1 interacts with Dynamin 2 and inhibits its GTPase activity; Dynamin 2 knockdown suppresses the PQBP1-knockdown ciliary phenotype. A XLID-causing WW domain mutation of PQBP1 disrupts both Dynamin 2 binding/inhibition and ciliogenesis.","method":"Immunofluorescence localization, in vivo cortical knockdown, co-immunoprecipitation (PQBP1-Dynamin 2), GTPase activity assay, epistasis (double knockdown), disease mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro GTPase assay, reciprocal co-IP, genetic epistasis, in vivo phenotype, disease mutant validation; multiple orthogonal methods","pmids":["23994472"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5-15kD reveals that the U5-15kD hydrophobic groove recognizes a YxxPxxVL motif in PQBP1. Mutations within this motif abolish interaction in vitro and cause loss-of-function. All known PQBP1 frameshift mutations causing mental retardation eliminate the YxxPxxVL motif, providing a molecular mechanism for intellectual disability.","method":"X-ray crystallography, in vitro mutagenesis, binding assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis validation, directly explains disease mutations","pmids":["24781215"],"is_preprint":false},{"year":2014,"finding":"Conditional knockout of Pqbp1 in neural stem progenitor cells (NSPCs) causes microcephaly by elongating the M phase of the cell cycle, reducing the NSPC pool. Gene expression changes in NSPCs affect anaphase-promoting complex genes via aberrant transcription and RNA splicing. Exogenous Apc4 rescues the cell cycle and proliferation phenotypes. In utero AAV-PQBP1 gene therapy at E10 rescues microcephaly and behavioral abnormalities.","method":"Conditional knockout mouse, cell cycle analysis (live imaging/flow), gene expression profiling, rescue by AAV and by Apc4 overexpression","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific cellular phenotype, gene expression profiling, genetic rescue, in vivo gene therapy rescue; multiple orthogonal methods","pmids":["25070536"],"is_preprint":false},{"year":2014,"finding":"PQBP1 knockdown in Xenopus embryos inhibits FGF target gene induction (but not BMP, Nodal, or Wnt) and changes alternative splicing of FGFR2 transcripts, altering incorporation of cassette exons that generate receptor variants with different ligand specificities. The splicing factor WBP11 acts as a PQBP1 binding partner with similar developmental functions.","method":"Morpholino knockdown in Xenopus, RT-PCR splicing analysis, animal cap explant assay, in situ hybridization","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with pathway-specific rescue, splicing analysis, single lab","pmids":["25209246"],"is_preprint":false},{"year":2015,"finding":"PQBP1 directly binds reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate immune response in dendritic cells. MDDCs from Renpenning syndrome patients with PQBP1 mutations show severely attenuated innate immune responses to HIV-1.","method":"Targeted RNAi screen in primary MDDCs, direct DNA binding assay, co-immunoprecipitation (PQBP1-cGAS), IRF3 activation assay, patient-derived MDDC functional assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay, reciprocal co-IP, functional screen, patient cell validation; multiple orthogonal methods in a high-impact publication","pmids":["26046437"],"is_preprint":false},{"year":2015,"finding":"In Drosophila photoreceptor cells, cytoplasmic dPQBP1 regulates translation of specific mRNAs (including Chaoptin) by interacting with dFMR1, which binds target mRNAs and facilitates their assembly into translating ribosomes. This function is conserved for human PQBP1 and FMRP. Loss of dPQBP1 causes defective rhabdomere morphogenesis due to impaired Chaoptin translation.","method":"Co-immunoprecipitation (dPQBP1-dFMR1), polysome fractionation, immunostaining, genetic KO in Drosophila, rescue experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, polysome fractionation, KO phenotype; single lab, Drosophila ortholog","pmids":["26002102"],"is_preprint":false},{"year":2016,"finding":"Binding of PQBP1 to its partner WBP11 (via the WW domain) allosterically reduces the binding affinity of PQBP1 to U5-15kD (via its C-terminal YxxPxxVL motif), demonstrating negative allosteric modulation between the two PQBP1 interaction surfaces.","method":"In vitro binding assays (surface plasmon resonance, pulldown), NMR","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro binding assays with biophysical methods, single lab, single paper","pmids":["27314904"],"is_preprint":false},{"year":2017,"finding":"PQBP1 mutations c.459_462delAGAG and c.463_464dupAG encode a new C-terminal epitope that preferentially binds non-phosphorylated FMRP and promotes its ubiquitin-mediated degradation. This impairs FMRP function, up-regulates targets such as MAP1B, and disrupts FMRP-dependent synaptic scaling. In Drosophila NMJ, the c.463_464dupAG transgene causes synaptic overgrowth rescued by dFMRP expression, supporting a gain-of-function pathogenic mechanism.","method":"Co-immunoprecipitation, ubiquitination assay, synaptic scaling assay in primary neurons, Drosophila NMJ transgenic rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, ubiquitination assay, electrophysiology/synaptic scaling, in vivo Drosophila rescue; multiple orthogonal methods","pmids":["28073926"],"is_preprint":false},{"year":2018,"finding":"SRRM2 phosphorylation at Ser1068 (by ERK1/2) inhibits its nuclear translocation and interaction with T-complex protein subunit α. SRRM2 deficiency destabilizes PQBP1 in neurons and impairs splicing of synapse-related genes. Conditional knockout of PQBP1 in neurons recapitulates synapse and splicing phenotypes. AAV-PQBP1 rescues RNA splicing, synapse phenotype, and cognitive decline in two AD mouse models.","method":"Phospho-proteomics, PQBP1-conditional KO mouse, RNA-seq (splicing), AAV gene therapy rescue, co-immunoprecipitation","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, multiple orthogonal methods (phosphoproteomics, RNA-seq, co-IP, AAV rescue), in vivo validation","pmids":["30283027"],"is_preprint":false},{"year":2020,"finding":"PQBP1 facilitates the nuclear import of the splicing factor TXNL4A via a piggyback mechanism through the nuclear import receptor karyopherin β2. The PQBP1-TXNL4A interaction requires the C-terminal YxxPxxVL motif; the XLID missense mutation P244L in PQBP1 disrupts this interaction and consequently mislocalizes TXNL4A.","method":"Recombinant protein expression, in vitro binding assays, immunofluorescence microscopy in HeLa cells, disease mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding assays, cellular localization experiments, mutant validation; multiple orthogonal methods in one study","pmids":["32041777"],"is_preprint":false},{"year":2021,"finding":"PQBP1 senses extrinsic tau (3R/4R) proteins by direct interaction and triggers an innate immune response through the cGAS-STING pathway, leading to NFκB nuclear translocation, NFκB-dependent inflammatory gene transcription, and microglial brain inflammation. Microglia-specific, tamoxifen-inducible depletion of PQBP1 in vitro and in vivo abolishes tau-induced inflammation and prevents cognitive impairment in mice.","method":"Direct protein-protein interaction assay (tau-PQBP1), cGAS-STING pathway activation assay, microglia-specific conditional KO (tamoxifen-inducible), in vivo mouse cognition tests, NFκB reporter assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay, conditional cell-type-specific KO in vivo, multiple pathway readouts, cognitive phenotype; multiple orthogonal methods","pmids":["34782623"],"is_preprint":false},{"year":2021,"finding":"PQBP1 specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56, thereby promoting translational elongation. Loss of PQBP1 reduces global protein synthesis. PQBP1 regulates hippocampal mGluR-dependent long-term depression and associated behaviors through this eEF2K/eEF2 pathway.","method":"Co-immunoprecipitation, in vitro kinase assay, puromycin incorporation assay (global translation), mGluR-LTD electrophysiology, PQBP1 knockout/knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, co-IP, translation assay, electrophysiology, KO; multiple orthogonal methods in one rigorous study","pmids":["33662272"],"is_preprint":false},{"year":2021,"finding":"LATS2 (Hippo pathway kinase) interacts with PQBP1 and enhances cGAS-STING-mediated innate immune response to HIV-1 reverse-transcribed DNA, upregulating type-I interferon and cytokines. This function is independent of canonical YAP/TAZ downstream signaling and involves LATS2 kinase activity with a potential phosphorylation site on PQBP1.","method":"Co-immunoprecipitation (LATS2-PQBP1), kinase activity assay, interferon reporter assay, HIV-1 infection assay, phosphorylation site identification","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, kinase assay, functional readout; single lab, phosphorylation site not fully validated","pmids":["34385679"],"is_preprint":false},{"year":2022,"finding":"Upon HIV-1 infection, PQBP1 decorates the intact viral capsid as a primary recognition step, and this capsid binding is required for subsequent cGAS recruitment to the capsid in a PQBP1-dependent manner. This positions cGAS at the site of viral DNA generation during reverse transcription and capsid disassembly.","method":"Proximity ligation assay, co-immunoprecipitation, capsid binding assay, fluorescence microscopy, HIV-1 infection time-course experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct capsid binding demonstrated, cGAS recruitment shown in PQBP1-dependent manner, multiple imaging and biochemical methods, high-impact journal","pmids":["35809572"],"is_preprint":false},{"year":2023,"finding":"PQBP1 binds to HIV-1 capsids through charge-complementing contacts between acidic residues in its N-terminal region and an arginine ring in the central channel of the HIV-1 CA hexamer, revealing the molecular basis of capsid recognition.","method":"Structural analysis (cryo-EM/crystallography of CA hexamer), mutagenesis, in vitro capsid binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination combined with mutagenesis and binding assay, single lab","pmids":["38128824"],"is_preprint":false},{"year":2023,"finding":"PQBP1 promotes exon 9 inclusion of Numb via alternative splicing in striatal progenitors, maintaining a variant that mediates progenitor proliferation. PQBP1 deletion in striatal progenitors causes reduced proliferation, increased differentiation, and depleted progenitor pool leading to defective striatal development.","method":"Conditional KO mouse (striatum-specific), RNA-seq splicing analysis, RT-PCR validation, BrdU/EdU proliferation assay, in vivo histology","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, RNA-seq splicing, cellular phenotype; single lab","pmids":["36943865"],"is_preprint":false},{"year":2024,"finding":"PQBP1 preferentially binds to exon regions of pre-mRNAs and promotes BAX exon 2 skipping in ovarian cancer cells, generating a truncated BAX isoform subject to nonsense-mediated mRNA decay, thereby reducing apoptosis and promoting tumor progression. PQBP1 depletion or splice-switching antisense oligonucleotides restore BAX exon 2 inclusion and BAX expression, inhibiting tumor growth.","method":"spyCLIP-seq (direct RNA binding), RNA-seq (alternative splicing), PQBP1 knockdown/overexpression, antisense oligonucleotide rescue, in vivo xenograft tumor model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CLIP-seq direct binding, RNA-seq, genetic rescue, in vivo tumor model; multiple orthogonal methods","pmids":["38342602"],"is_preprint":false},{"year":2024,"finding":"PQBP1 directly interacts with upstream UGUA elements in pre-mRNAs and impedes recruitment of the CFIm complex, thereby influencing polyadenylation site selection within cell-cycle-related genes in neural progenitor cells. Loss of PQBP1 shifts alternative polyadenylation profiles and disrupts the balance between NPC proliferation and differentiation.","method":"Multi-omics (CLIP-seq, RNA-seq, APA-seq), PQBP1 knockdown/KO, CFIm complex co-immunoprecipitation, in vitro binding assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CLIP-seq direct binding, multi-omics, co-IP, functional phenotype; multiple orthogonal methods","pmids":["39037895"],"is_preprint":false},{"year":2026,"finding":"The PQBP1 Y65C missense mutation causes PQBP1 misfolding and reduced protein levels (partial loss-of-function), impairing apical progenitor proliferation and microcephaly in knock-in mice. Additionally, Y65C causes a gain-of-function by enhancing interactions with core components of the mRNA 3' end processing machinery, preserving proliferative alternative polyadenylation profiles that interfere with the apical-to-basal progenitor transition.","method":"Pqbp1-Y65C knock-in mice, brain progenitor cell analysis (IHC, EdU labeling), co-immunoprecipitation (Y65C mutant with 3' end processing machinery), APA profiling, protein stability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model, co-IP with disease mutant, APA profiling, multiple cellular phenotype readouts; multiple orthogonal methods","pmids":["41507200"],"is_preprint":false},{"year":2008,"finding":"PQBP1 overexpression induces nuclear inclusions whose formation is dramatically enhanced by co-expression of the pre-mRNA splicing factor SIPP1. Site-directed mutagenesis shows that multiple independent interaction sites between SIPP1 and PQBP1 are required for inclusion facilitation. The inclusions are highly dynamic, do not colocalize with known nuclear structures, and their formation does not require energy.","method":"Transfection/overexpression, immunofluorescence, site-directed mutagenesis, FRAP (fluorescence recovery after photobleaching)","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mutagenesis of interaction sites, FRAP, immunofluorescence; single lab","pmids":["18599155"],"is_preprint":false},{"year":2009,"finding":"PQBP1 knockdown in mice impairs anxiety-related cognition and reduces c-fos upregulation and histone H3 acetylation in amygdala, prefrontal cortex, and hippocampus after behavioral tests. The HDAC inhibitor 4-phenylbutyric acid rescues gene expression and behavioral phenotypes, linking PQBP1 to chromatin-dependent gene expression in cognitive circuits.","method":"Transgenic siRNA knockdown mouse, behavioral tests (open field, EPM, novel object recognition), immunohistochemistry (c-fos, H3 acetylation), pharmacological rescue (HDAC inhibitor)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD mouse model, behavioral and molecular phenotype, pharmacological rescue; single lab","pmids":["19661183"],"is_preprint":false},{"year":2019,"finding":"Frameshift PQBP-1 mutants K192Sfs*7 and R153Sfs*41 form stable dimers (unlike monomeric wild-type), have more folded content and higher thermal stability, and show significantly weakened binding to phosphorylated RNA Pol II CTD heptapeptide (YpSPTpSPS), suggesting their toxicity arises from loss of transcriptional regulatory function rather than aggregation.","method":"Small-angle X-ray scattering (SAXS), biophysical characterization, fluorescence anisotropy binding assay with labeled Pol II CTD peptide","journal":"Journal of structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biophysical characterization and binding assay, single lab, single paper","pmids":["30951824"],"is_preprint":false},{"year":2025,"finding":"High-fat diet (HFD) suppresses PPARγ-mediated transcriptional expression of PQBP1, leading to alternative splicing changes in synapse-related genes (CASK, Cacnb1, Cyfip2, Syt1) that impair presynaptic vesicle release and cognitive function. AAV-PQBP1 or AAVs expressing individual target genes rescue synapse and cognitive dysfunctions in HFD mice.","method":"RNA-seq (alternative splicing), chromatin assays, primary neuron electrophysiology/vesicle release assay, AAV rescue in vivo, immunohistochemistry","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq, functional vesicle release assay, in vivo AAV rescue; preprint, single lab","pmids":["40502014"],"is_preprint":true}],"current_model":"PQBP1 is a multifunctional nuclear-cytoplasmic protein that (1) regulates pre-mRNA alternative splicing and alternative polyadenylation by associating with spliceosomal components (U5-15kD via a YxxPxxVL motif, SF3B1, WBP11/SIPP1, TXNL4A) and by blocking CFIm complex recruitment to UGUA elements; (2) in the cytoplasm, binds non-phosphorylated eEF2 to suppress eEF2K-mediated Thr56 phosphorylation, promoting translational elongation and mGluR-LTD; (3) acts as an innate immune sensor by decorating intact HIV-1 capsids (via N-terminal acidic residues contacting the CA hexamer arginine ring), recruiting cGAS at the site of reverse transcription to initiate an IRF3-dependent interferon response, and by directly binding exogenous tau to activate cGAS-STING-NFκB-driven microglial inflammation; (4) inhibits transcriptional activation (e.g., by Brn-2 and RNA Pol II) and, when bound by expanded-polyglutamine proteins such as mutant ataxin-1, is redirected to the Pol II C-terminal domain, suppressing transcription and triggering apoptosis; and (5) interacts with Dynamin 2 to inhibit its GTPase activity and promote neuronal ciliogenesis, with XLID-causing WW domain mutations disrupting this function."},"narrative":{"mechanistic_narrative":"PQBP1 is a multifunctional polar-amino-acid- and WW-domain-containing protein that operates in both the nucleus and cytoplasm to couple RNA processing, translational control, and innate immune sensing to neuronal development and survival [PMID:10332029, PMID:23512658]. In the nucleus it acts as an alternative-splicing and alternative-polyadenylation effector: it binds spliceosomal factors including the U2 snRNP component SF3B1, WBP11/SIPP1, and the U5-15kD protein, with the C-terminal YxxPxxVL motif docking into the U5-15kD hydrophobic groove, and its loss reshapes splicing of target transcripts and impairs dendritic and neurite outgrowth [PMID:20410308, PMID:23512658, PMID:24781215, PMID:18599155]. PQBP1 binds exonic regions of pre-mRNAs directly and also engages upstream UGUA elements to block CFIm recruitment, thereby controlling poly(A)-site selection in cell-cycle and progenitor genes; through these activities it governs splicing decisions such as Numb exon 9 inclusion and BAX exon 2 skipping that set the balance between progenitor proliferation and differentiation or apoptosis [PMID:38342602, PMID:39037895, PMID:41507200]. It additionally chaperones nuclear import of the splicing factor TXNL4A by a karyopherin-β2 piggyback mechanism [PMID:32041777]. In the cytoplasm PQBP1 binds non-phosphorylated eEF2 to suppress eEF2K-mediated Thr56 phosphorylation, promoting translational elongation and hippocampal mGluR-dependent long-term depression, and partners with FMRP/dFMR1 in neuronal RNA granules to control translation of specific mRNAs [PMID:26002102, PMID:33662272]. PQBP1 also serves as an innate immune sensor that decorates intact HIV-1 capsids—through charge-complementing contacts between its N-terminal acidic residues and the arginine ring of the CA hexamer—and recruits cGAS to drive an IRF3-dependent interferon response, and it directly binds extracellular tau to activate cGAS-STING-NFκB-driven microglial inflammation [PMID:26046437, PMID:34782623, PMID:35809572, PMID:38128824]. Finally, PQBP1 binds polyglutamine tracts and represses transcription, an activity hijacked by expanded-polyglutamine ataxin-1 that redirects PQBP1 to the RNA Pol II C-terminal domain to suppress transcription and trigger apoptosis [PMID:10332029, PMID:12062018]. PQBP1 mutations cause X-linked intellectual disability syndromes (Golabi-Ito-Hall and Renpenning), where loss of splicing-factor and ligand binding, mislocalization of partners, or gain-of-function gains of new binding surfaces produce microcephaly and neuronal dysfunction [PMID:20410308, PMID:24781215, PMID:32041777, PMID:41507200].","teleology":[{"year":1999,"claim":"Established PQBP1 as a nuclear polyglutamine-binding protein that represses transcription, defining its founding activity and domain architecture.","evidence":"Yeast two-hybrid, in vitro binding, transcription reporter and viability assays","pmids":["10332029"],"confidence":"High","gaps":["Did not define direct transcriptional mechanism","Physiological splicing role not yet known"]},{"year":2002,"claim":"Showed that expanded-polyglutamine ataxin-1 enhances PQBP1 binding to the Pol II CTD, reducing CTD phosphorylation and inducing apoptosis, linking PQBP1 to polyQ disease pathology.","evidence":"Co-immunoprecipitation, transcription and apoptosis assays in cell lines","pmids":["12062018"],"confidence":"High","gaps":["Did not establish whether this mechanism operates in neurons in vivo"]},{"year":2003,"claim":"Demonstrated that excess PQBP1 alone causes progressive neurodegeneration in mice, showing dosage sensitivity of PQBP1 activity.","evidence":"Transgenic mouse overexpression with histopathology","pmids":["12651867"],"confidence":"Medium","gaps":["Molecular basis of toxicity not resolved","Single lab, ubiquitous overexpression"]},{"year":2008,"claim":"Identified SIPP1/WBP11 as a PQBP1 partner driving dynamic nuclear inclusion formation, pointing toward a splicing-related nuclear function.","evidence":"Overexpression, immunofluorescence, site-directed mutagenesis, FRAP","pmids":["18599155"],"confidence":"Medium","gaps":["Functional consequence of inclusions unknown","Relationship to physiological splicing unclear"]},{"year":2009,"claim":"Linked PQBP1 to cognition by showing knockdown impairs anxiety-related behavior and chromatin-associated gene induction, rescued by an HDAC inhibitor.","evidence":"siRNA knockdown mouse, behavioral tests, IHC, pharmacological rescue","pmids":["19661183"],"confidence":"Medium","gaps":["Direct chromatin mechanism not defined","Connection to splicing function not made"]},{"year":2010,"claim":"Connected a WW-domain disease mutation (Y65C, Golabi-Ito-Hall) to loss of proline-rich ligand binding and reduced splicing efficiency, establishing splicing dysfunction as a disease mechanism.","evidence":"In vitro binding with mutagenesis, patient lymphoblast co-IP, RT-PCR splicing assay","pmids":["20410308"],"confidence":"High","gaps":["Genome-wide splicing targets not yet mapped"]},{"year":2011,"claim":"Revealed a cytoplasmic PQBP1 pool in RNA-dependent complexes with FMRP and RNA-binding/transport proteins, including stress-granule association, expanding its role beyond the nucleus.","evidence":"Co-IP, immunofluorescence, RNase-dependency, stress-granule induction","pmids":["21933836"],"confidence":"Medium","gaps":["Direct mRNA targets of cytoplasmic complexes undefined","Functional consequence of SG association unclear"]},{"year":2013,"claim":"Defined PQBP1 as a genome-wide alternative-splicing effector acting through SF3B1, and showed disease mutants fail to support neurite outgrowth, unifying its biochemistry with neuronal phenotype.","evidence":"MS interactome, RIP, RNA-seq, neuronal knockdown, mutant complementation","pmids":["23512658"],"confidence":"High","gaps":["Direct RNA-binding specificity not yet mapped at nucleotide resolution"]},{"year":2013,"claim":"Established a non-splicing cytoplasmic role: PQBP1 inhibits Dynamin 2 GTPase to promote neuronal ciliogenesis, with a WW-domain XLID mutation disrupting this function.","evidence":"Localization, in vivo cortical knockdown, co-IP, GTPase assay, epistasis, mutant analysis","pmids":["23994472"],"confidence":"High","gaps":["Regulation of the Dynamin 2 interaction not defined","Relationship to splicing role not integrated"]},{"year":2014,"claim":"Crystal structure of the PQBP1–U5-15kD complex defined the YxxPxxVL recognition motif and explained why frameshift XLID mutations that delete this motif are pathogenic.","evidence":"X-ray crystallography, mutagenesis, binding assay","pmids":["24781215"],"confidence":"High","gaps":["Did not address how WW-domain partners influence this interaction"]},{"year":2014,"claim":"Showed PQBP1 loss causes microcephaly by lengthening NSPC M phase via APC gene dysregulation, with Apc4 and in utero AAV-PQBP1 rescuing the phenotype, connecting splicing/transcription control to brain size.","evidence":"Conditional KO mouse, cell-cycle imaging, expression profiling, genetic and gene-therapy rescue","pmids":["25070536"],"confidence":"High","gaps":["Whether APC effects are direct splicing targets not fully resolved"]},{"year":2014,"claim":"Demonstrated developmental specificity by showing PQBP1 controls FGFR2 alternative splicing and FGF target induction in Xenopus, with WBP11 as a partner.","evidence":"Morpholino knockdown, RT-PCR splicing, animal cap assays, in situ hybridization","pmids":["25209246"],"confidence":"Medium","gaps":["Mammalian conservation of FGFR2 regulation untested","Single lab"]},{"year":2015,"claim":"Identified PQBP1 as an innate immune sensor that binds reverse-transcribed HIV-1 DNA and recruits cGAS for an IRF3 response, with patient cells showing attenuated immunity.","evidence":"RNAi screen in primary MDDCs, DNA binding, cGAS co-IP, IRF3 assay, patient cell validation","pmids":["26046437"],"confidence":"High","gaps":["Initial step of viral recognition not yet defined","How PQBP1 reaches viral DNA unclear"]},{"year":2015,"claim":"Established a conserved cytoplasmic translational role: PQBP1/dPQBP1 partners with FMRP to control translation of specific mRNAs such as Chaoptin, required for photoreceptor morphogenesis.","evidence":"Co-IP, polysome fractionation, Drosophila KO and rescue","pmids":["26002102"],"confidence":"Medium","gaps":["Mechanism of mRNA selection undefined","Drosophila ortholog model"]},{"year":2016,"claim":"Revealed negative allosteric coupling between PQBP1's WW domain (WBP11) and C-terminal (U5-15kD) interfaces, showing the two RNA-processing partnerships are mutually regulated.","evidence":"SPR, pulldown, NMR","pmids":["27314904"],"confidence":"Medium","gaps":["In vivo relevance of the allostery untested","Single biophysical study"]},{"year":2017,"claim":"Showed specific frameshift mutations create a new epitope that binds and degrades non-phosphorylated FMRP, defining a gain-of-function disease mechanism affecting synaptic scaling.","evidence":"Co-IP, ubiquitination assay, synaptic scaling, Drosophila NMJ rescue","pmids":["28073926"],"confidence":"High","gaps":["Whether all frameshift mutations act this way unclear"]},{"year":2018,"claim":"Placed PQBP1 downstream of SRRM2 stability and linked PQBP1 loss to synapse-gene mis-splicing in Alzheimer's models, with AAV-PQBP1 rescuing cognition.","evidence":"Phosphoproteomics, conditional KO, RNA-seq, co-IP, AAV rescue in AD models","pmids":["30283027"],"confidence":"High","gaps":["Direct PQBP1 binding to affected transcripts not all mapped"]},{"year":2019,"claim":"Showed XLID frameshift mutants form stable dimers and lose binding to phosphorylated Pol II CTD, arguing toxicity arises from loss of transcriptional regulation rather than aggregation.","evidence":"SAXS, biophysical characterization, fluorescence anisotropy CTD binding","pmids":["30951824"],"confidence":"Medium","gaps":["Cellular consequence of dimerization untested","Single in vitro study"]},{"year":2020,"claim":"Defined PQBP1 as a nuclear-import chaperone for TXNL4A via karyopherin-β2 piggyback, with the P244L XLID mutation disrupting this transport.","evidence":"Recombinant binding assays, immunofluorescence, disease-mutant analysis","pmids":["32041777"],"confidence":"High","gaps":["Whether import defect drives disease phenotypes in vivo not shown"]},{"year":2021,"claim":"Established a direct translational-elongation mechanism: PQBP1 binds non-phosphorylated eEF2 to block eEF2K phosphorylation, promoting elongation and mGluR-LTD.","evidence":"Co-IP, in vitro kinase assay, puromycin labeling, mGluR-LTD electrophysiology, KO","pmids":["33662272"],"confidence":"High","gaps":["How nuclear and cytoplasmic functions are partitioned unclear"]},{"year":2021,"claim":"Extended PQBP1 immune sensing to neurodegeneration by showing it directly binds extracellular tau to drive cGAS-STING-NFκB microglial inflammation, with microglial depletion preventing cognitive impairment.","evidence":"Direct binding, cGAS-STING readouts, microglia-specific inducible KO, cognition tests","pmids":["34782623"],"confidence":"High","gaps":["Structural basis of tau recognition undefined"]},{"year":2021,"claim":"Identified LATS2 as a kinase partner enhancing PQBP1-dependent cGAS-STING responses to HIV-1, independent of canonical Hippo YAP/TAZ signaling.","evidence":"Co-IP, kinase assay, interferon reporter, HIV-1 infection","pmids":["34385679"],"confidence":"Medium","gaps":["PQBP1 phosphorylation site not fully validated","Single lab"]},{"year":2022,"claim":"Showed that PQBP1 decorates the intact HIV-1 capsid as the primary recognition event upstream of cGAS recruitment, resolving how cGAS reaches viral DNA.","evidence":"Proximity ligation, co-IP, capsid binding, imaging time-course","pmids":["35809572"],"confidence":"High","gaps":["Atomic basis of capsid contact not yet defined"]},{"year":2023,"claim":"Provided the structural basis for capsid recognition, mapping N-terminal acidic residues of PQBP1 to the arginine ring of the CA hexamer central channel.","evidence":"Structural analysis of CA hexamer, mutagenesis, in vitro capsid binding","pmids":["38128824"],"confidence":"High","gaps":["How capsid binding triggers cGAS conformational activation unresolved"]},{"year":2023,"claim":"Showed PQBP1 promotes Numb exon 9 inclusion to maintain striatal progenitor proliferation, linking a defined splicing event to neurodevelopmental outcome.","evidence":"Striatum-specific conditional KO, RNA-seq, RT-PCR, proliferation assays, histology","pmids":["36943865"],"confidence":"Medium","gaps":["Whether Numb mis-splicing alone explains the phenotype untested"]},{"year":2024,"claim":"Demonstrated PQBP1 binds exonic pre-mRNA regions and drives BAX exon 2 skipping to evade apoptosis, defining a pro-tumorigenic splicing role and an ASO therapeutic strategy.","evidence":"spyCLIP-seq, RNA-seq, knockdown/overexpression, ASO rescue, xenograft","pmids":["38342602"],"confidence":"High","gaps":["Generality across cancer types not established"]},{"year":2024,"claim":"Established a new RNA-processing axis: PQBP1 binds UGUA elements and blocks CFIm recruitment to control alternative polyadenylation in cell-cycle genes governing NPC fate.","evidence":"CLIP-seq, RNA-seq, APA-seq, CFIm co-IP, in vitro binding, knockdown/KO","pmids":["39037895"],"confidence":"High","gaps":["How splicing and APA functions are coordinated unclear"]},{"year":2026,"claim":"Resolved that the Y65C mutation combines partial loss-of-function (misfolding, reduced levels) with gain-of-function enhanced binding to 3'-end processing machinery, distorting APA profiles and progenitor transitions.","evidence":"Y65C knock-in mice, progenitor analysis, mutant co-IP, APA profiling, stability assays","pmids":["41507200"],"confidence":"High","gaps":["Relative contribution of loss vs gain to human disease severity unquantified"]},{"year":null,"claim":"How PQBP1's distinct nuclear (splicing/APA/transcription), cytoplasmic (translation), and immune-sensing activities are partitioned and coordinated within a single neuron, and which are decisive for each XLID phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model partitioning the functions by compartment or stimulus","Which activity dominates in each disease context is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[22,23,5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10,16,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,17]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[16,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,23,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,16,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,21,6]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,23]}],"complexes":["spliceosome (SF3B1/U5-15kD-associated)"],"partners":["SF3B1","WBP11","TXNL4A","CGAS","EEF2","DNM2","FMRP","LATS2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60828","full_name":"Polyglutamine-binding protein 1","aliases":["38 kDa nuclear protein containing a WW domain","Npw38","Polyglutamine tract-binding protein 1"],"length_aa":265,"mass_kda":30.5,"function":"Intrinsically disordered protein that acts as a scaffold, and which is involved in different processes, such as pre-mRNA splicing, transcription regulation, innate immunity and neuron development (PubMed:10198427, PubMed:10332029, PubMed:12062018, PubMed:20410308, PubMed:23512658). Interacts with splicing-related factors via the intrinsically disordered region and regulates alternative splicing of target pre-mRNA species (PubMed:10332029, PubMed:12062018, PubMed:20410308, PubMed:23512658). May suppress the ability of POU3F2 to transactivate the DRD1 gene in a POU3F2 dependent manner. Can activate transcription directly or via association with the transcription machinery (PubMed:10198427). May be involved in ATXN1 mutant-induced cell death (PubMed:12062018). The interaction with ATXN1 mutant reduces levels of phosphorylated RNA polymerase II large subunit (PubMed:12062018). Involved in the assembly of cytoplasmic stress granule, possibly by participating in the transport of neuronal RNA granules (PubMed:21933836). Also acts as an innate immune sensor of infection by retroviruses, such as HIV, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:26046437). Directly binds retroviral reverse-transcribed DNA in the cytosol and interacts with CGAS, leading to activate the cGAS-STING signaling pathway, triggering type-I interferon production (PubMed:26046437)","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasmic granule","url":"https://www.uniprot.org/uniprotkb/O60828/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PQBP1","classification":"Not Classified","n_dependent_lines":86,"n_total_lines":1208,"dependency_fraction":0.07119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PQBP1","total_profiled":1310},"omim":[{"mim_id":"618083","title":"WW-BINDING PROTEIN 11; WBP11","url":"https://www.omim.org/entry/618083"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"601556","title":"ATAXIN 1; ATXN1","url":"https://www.omim.org/entry/601556"},{"mim_id":"309500","title":"RENPENNING SYNDROME 1; RENS1","url":"https://www.omim.org/entry/309500"},{"mim_id":"300977","title":"SCHOLTE SYNDROME; SHLTS","url":"https://www.omim.org/entry/300977"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Primary cilium","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PQBP1"},"hgnc":{"alias_symbol":[],"prev_symbol":["RENS1","MRXS8","SHS","MRX55","MRX2","MRXS3"]},"alphafold":{"accession":"O60828","domains":[{"cath_id":"2.20.70","chopping":"39-87","consensus_level":"high","plddt":87.5057,"start":39,"end":87},{"cath_id":"1.20.5","chopping":"149-186","consensus_level":"medium","plddt":74.2092,"start":149,"end":186}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60828","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60828-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60828-F1-predicted_aligned_error_v6.png","plddt_mean":70.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PQBP1","jax_strain_url":"https://www.jax.org/strain/search?query=PQBP1"},"sequence":{"accession":"O60828","fasta_url":"https://rest.uniprot.org/uniprotkb/O60828.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60828/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60828"}},"corpus_meta":[{"pmid":"16442908","id":"PMC_16442908","title":"Left 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Overexpression suppresses cell growth and enhances susceptibility to stress. The protein contains a WW domain, polar amino acid repeat sequences essential for polyglutamine binding, a putative nuclear localization signal, and a C2 domain.\",\n      \"method\": \"Yeast two-hybrid screen (binding), in vitro binding assays, nuclear localization by immunofluorescence, transcription reporter assays, cell viability assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assay, transcription reporter, localization, cell survival), foundational paper replicated by subsequent work\",\n      \"pmids\": [\"10332029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mutant ataxin-1 (expanded polyglutamine) enhances PQBP-1 binding to the C-terminal domain of RNA polymerase II large subunit, reducing phosphorylated Pol II levels and transcription, and inducing apoptotic cell death. This interaction is positively influenced by expanded polyglutamine sequences.\",\n      \"method\": \"In vitro and in vivo binding assays, co-immunoprecipitation, transcription assays, apoptosis assays in cell lines\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, mechanistic transcription readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12062018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Transgenic overexpression of human PQBP-1 in mice causes a late-onset, progressive motor neuron disease-like phenotype with loss of Purkinje cells, granular cells in cerebellum, and spinal motor neurons, demonstrating that excessive PQBP-1 activity causes neuronal dysfunction.\",\n      \"method\": \"Transgenic mouse model (ubiquitous human PQBP-1 expression), behavioral analysis, histopathology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse with defined cellular phenotype, single lab\",\n      \"pmids\": [\"12651867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Y65C missense mutation in the WW domain of PQBP1 (Golabi-Ito-Hall syndrome) diminishes binding of the WW domain and full-length protein to proline-rich ligands. In patient-derived lymphoblasts, the PQBP1-Y65C/WBP11 splicing factor complex was compromised and pre-mRNA splicing efficiency was substantially decreased.\",\n      \"method\": \"In vitro binding assays with recombinant proteins, co-immunoprecipitation from patient lymphoblasts, RT-PCR splicing efficiency assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding assay with mutagenesis, patient cell validation, two orthogonal methods\",\n      \"pmids\": [\"20410308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PQBP1 localizes not only in nuclear speckles but also in a cytoplasmic pool in neurons, where it associates with RNA-binding proteins KSRP, SFPQ/PSF, DDX1, Caprin-1, and dynactin subunits p150(Glued) and p27 in RNA-dependent complexes. PQBP1 co-localizes with FMRP in neuronal RNA granules and relocalizes to stress granules upon arsenite-induced oxidative stress. The cellular distribution of PQBP1 influences stress granule assembly.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, RNA-dependency assay (RNase treatment), stress granule induction assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal co-IP, immunofluorescence localization with functional consequence (SG assembly), single lab\",\n      \"pmids\": [\"21933836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PQBP1 functions as an alternative mRNA splicing effector by associating with splicing factors including the U2 snRNP component SF3B1. Loss of PQBP1 reduces SF3B1 substrate mRNA association and causes significant changes in alternative splicing patterns. In primary neurons, PQBP1 depletion reduces dendritic outgrowth. Disease-linked PQBP1 mutants are deficient in splicing factor associations and cannot complement neurite outgrowth defects.\",\n      \"method\": \"Mass spectrometry (interactome), RIP (RNA immunoprecipitation), RNA-seq (splicing analysis), PQBP1 knockdown in primary neurons, neurite outgrowth assay, complementation with disease mutants\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS interactome, RIP, RNA-seq, KD phenotype, complementation), single lab with rigorous controls\",\n      \"pmids\": [\"23512658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PQBP1 is localized at the base of the neuronal primary cilium and its knockdown profoundly impairs ciliary morphogenesis in neurons and in the mouse cerebral cortex in vivo. PQBP1 interacts with Dynamin 2 and inhibits its GTPase activity; Dynamin 2 knockdown suppresses the PQBP1-knockdown ciliary phenotype. A XLID-causing WW domain mutation of PQBP1 disrupts both Dynamin 2 binding/inhibition and ciliogenesis.\",\n      \"method\": \"Immunofluorescence localization, in vivo cortical knockdown, co-immunoprecipitation (PQBP1-Dynamin 2), GTPase activity assay, epistasis (double knockdown), disease mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro GTPase assay, reciprocal co-IP, genetic epistasis, in vivo phenotype, disease mutant validation; multiple orthogonal methods\",\n      \"pmids\": [\"23994472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5-15kD reveals that the U5-15kD hydrophobic groove recognizes a YxxPxxVL motif in PQBP1. Mutations within this motif abolish interaction in vitro and cause loss-of-function. All known PQBP1 frameshift mutations causing mental retardation eliminate the YxxPxxVL motif, providing a molecular mechanism for intellectual disability.\",\n      \"method\": \"X-ray crystallography, in vitro mutagenesis, binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis validation, directly explains disease mutations\",\n      \"pmids\": [\"24781215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Conditional knockout of Pqbp1 in neural stem progenitor cells (NSPCs) causes microcephaly by elongating the M phase of the cell cycle, reducing the NSPC pool. Gene expression changes in NSPCs affect anaphase-promoting complex genes via aberrant transcription and RNA splicing. Exogenous Apc4 rescues the cell cycle and proliferation phenotypes. In utero AAV-PQBP1 gene therapy at E10 rescues microcephaly and behavioral abnormalities.\",\n      \"method\": \"Conditional knockout mouse, cell cycle analysis (live imaging/flow), gene expression profiling, rescue by AAV and by Apc4 overexpression\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific cellular phenotype, gene expression profiling, genetic rescue, in vivo gene therapy rescue; multiple orthogonal methods\",\n      \"pmids\": [\"25070536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PQBP1 knockdown in Xenopus embryos inhibits FGF target gene induction (but not BMP, Nodal, or Wnt) and changes alternative splicing of FGFR2 transcripts, altering incorporation of cassette exons that generate receptor variants with different ligand specificities. The splicing factor WBP11 acts as a PQBP1 binding partner with similar developmental functions.\",\n      \"method\": \"Morpholino knockdown in Xenopus, RT-PCR splicing analysis, animal cap explant assay, in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with pathway-specific rescue, splicing analysis, single lab\",\n      \"pmids\": [\"25209246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PQBP1 directly binds reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate immune response in dendritic cells. MDDCs from Renpenning syndrome patients with PQBP1 mutations show severely attenuated innate immune responses to HIV-1.\",\n      \"method\": \"Targeted RNAi screen in primary MDDCs, direct DNA binding assay, co-immunoprecipitation (PQBP1-cGAS), IRF3 activation assay, patient-derived MDDC functional assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay, reciprocal co-IP, functional screen, patient cell validation; multiple orthogonal methods in a high-impact publication\",\n      \"pmids\": [\"26046437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila photoreceptor cells, cytoplasmic dPQBP1 regulates translation of specific mRNAs (including Chaoptin) by interacting with dFMR1, which binds target mRNAs and facilitates their assembly into translating ribosomes. This function is conserved for human PQBP1 and FMRP. Loss of dPQBP1 causes defective rhabdomere morphogenesis due to impaired Chaoptin translation.\",\n      \"method\": \"Co-immunoprecipitation (dPQBP1-dFMR1), polysome fractionation, immunostaining, genetic KO in Drosophila, rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, polysome fractionation, KO phenotype; single lab, Drosophila ortholog\",\n      \"pmids\": [\"26002102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Binding of PQBP1 to its partner WBP11 (via the WW domain) allosterically reduces the binding affinity of PQBP1 to U5-15kD (via its C-terminal YxxPxxVL motif), demonstrating negative allosteric modulation between the two PQBP1 interaction surfaces.\",\n      \"method\": \"In vitro binding assays (surface plasmon resonance, pulldown), NMR\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro binding assays with biophysical methods, single lab, single paper\",\n      \"pmids\": [\"27314904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PQBP1 mutations c.459_462delAGAG and c.463_464dupAG encode a new C-terminal epitope that preferentially binds non-phosphorylated FMRP and promotes its ubiquitin-mediated degradation. This impairs FMRP function, up-regulates targets such as MAP1B, and disrupts FMRP-dependent synaptic scaling. In Drosophila NMJ, the c.463_464dupAG transgene causes synaptic overgrowth rescued by dFMRP expression, supporting a gain-of-function pathogenic mechanism.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, synaptic scaling assay in primary neurons, Drosophila NMJ transgenic rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, ubiquitination assay, electrophysiology/synaptic scaling, in vivo Drosophila rescue; multiple orthogonal methods\",\n      \"pmids\": [\"28073926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SRRM2 phosphorylation at Ser1068 (by ERK1/2) inhibits its nuclear translocation and interaction with T-complex protein subunit α. SRRM2 deficiency destabilizes PQBP1 in neurons and impairs splicing of synapse-related genes. Conditional knockout of PQBP1 in neurons recapitulates synapse and splicing phenotypes. AAV-PQBP1 rescues RNA splicing, synapse phenotype, and cognitive decline in two AD mouse models.\",\n      \"method\": \"Phospho-proteomics, PQBP1-conditional KO mouse, RNA-seq (splicing), AAV gene therapy rescue, co-immunoprecipitation\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, multiple orthogonal methods (phosphoproteomics, RNA-seq, co-IP, AAV rescue), in vivo validation\",\n      \"pmids\": [\"30283027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PQBP1 facilitates the nuclear import of the splicing factor TXNL4A via a piggyback mechanism through the nuclear import receptor karyopherin β2. The PQBP1-TXNL4A interaction requires the C-terminal YxxPxxVL motif; the XLID missense mutation P244L in PQBP1 disrupts this interaction and consequently mislocalizes TXNL4A.\",\n      \"method\": \"Recombinant protein expression, in vitro binding assays, immunofluorescence microscopy in HeLa cells, disease mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding assays, cellular localization experiments, mutant validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"32041777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PQBP1 senses extrinsic tau (3R/4R) proteins by direct interaction and triggers an innate immune response through the cGAS-STING pathway, leading to NFκB nuclear translocation, NFκB-dependent inflammatory gene transcription, and microglial brain inflammation. Microglia-specific, tamoxifen-inducible depletion of PQBP1 in vitro and in vivo abolishes tau-induced inflammation and prevents cognitive impairment in mice.\",\n      \"method\": \"Direct protein-protein interaction assay (tau-PQBP1), cGAS-STING pathway activation assay, microglia-specific conditional KO (tamoxifen-inducible), in vivo mouse cognition tests, NFκB reporter assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay, conditional cell-type-specific KO in vivo, multiple pathway readouts, cognitive phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"34782623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PQBP1 specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56, thereby promoting translational elongation. Loss of PQBP1 reduces global protein synthesis. PQBP1 regulates hippocampal mGluR-dependent long-term depression and associated behaviors through this eEF2K/eEF2 pathway.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, puromycin incorporation assay (global translation), mGluR-LTD electrophysiology, PQBP1 knockout/knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, co-IP, translation assay, electrophysiology, KO; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"33662272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LATS2 (Hippo pathway kinase) interacts with PQBP1 and enhances cGAS-STING-mediated innate immune response to HIV-1 reverse-transcribed DNA, upregulating type-I interferon and cytokines. This function is independent of canonical YAP/TAZ downstream signaling and involves LATS2 kinase activity with a potential phosphorylation site on PQBP1.\",\n      \"method\": \"Co-immunoprecipitation (LATS2-PQBP1), kinase activity assay, interferon reporter assay, HIV-1 infection assay, phosphorylation site identification\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, kinase assay, functional readout; single lab, phosphorylation site not fully validated\",\n      \"pmids\": [\"34385679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upon HIV-1 infection, PQBP1 decorates the intact viral capsid as a primary recognition step, and this capsid binding is required for subsequent cGAS recruitment to the capsid in a PQBP1-dependent manner. This positions cGAS at the site of viral DNA generation during reverse transcription and capsid disassembly.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, capsid binding assay, fluorescence microscopy, HIV-1 infection time-course experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct capsid binding demonstrated, cGAS recruitment shown in PQBP1-dependent manner, multiple imaging and biochemical methods, high-impact journal\",\n      \"pmids\": [\"35809572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PQBP1 binds to HIV-1 capsids through charge-complementing contacts between acidic residues in its N-terminal region and an arginine ring in the central channel of the HIV-1 CA hexamer, revealing the molecular basis of capsid recognition.\",\n      \"method\": \"Structural analysis (cryo-EM/crystallography of CA hexamer), mutagenesis, in vitro capsid binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination combined with mutagenesis and binding assay, single lab\",\n      \"pmids\": [\"38128824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PQBP1 promotes exon 9 inclusion of Numb via alternative splicing in striatal progenitors, maintaining a variant that mediates progenitor proliferation. PQBP1 deletion in striatal progenitors causes reduced proliferation, increased differentiation, and depleted progenitor pool leading to defective striatal development.\",\n      \"method\": \"Conditional KO mouse (striatum-specific), RNA-seq splicing analysis, RT-PCR validation, BrdU/EdU proliferation assay, in vivo histology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, RNA-seq splicing, cellular phenotype; single lab\",\n      \"pmids\": [\"36943865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PQBP1 preferentially binds to exon regions of pre-mRNAs and promotes BAX exon 2 skipping in ovarian cancer cells, generating a truncated BAX isoform subject to nonsense-mediated mRNA decay, thereby reducing apoptosis and promoting tumor progression. PQBP1 depletion or splice-switching antisense oligonucleotides restore BAX exon 2 inclusion and BAX expression, inhibiting tumor growth.\",\n      \"method\": \"spyCLIP-seq (direct RNA binding), RNA-seq (alternative splicing), PQBP1 knockdown/overexpression, antisense oligonucleotide rescue, in vivo xenograft tumor model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CLIP-seq direct binding, RNA-seq, genetic rescue, in vivo tumor model; multiple orthogonal methods\",\n      \"pmids\": [\"38342602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PQBP1 directly interacts with upstream UGUA elements in pre-mRNAs and impedes recruitment of the CFIm complex, thereby influencing polyadenylation site selection within cell-cycle-related genes in neural progenitor cells. Loss of PQBP1 shifts alternative polyadenylation profiles and disrupts the balance between NPC proliferation and differentiation.\",\n      \"method\": \"Multi-omics (CLIP-seq, RNA-seq, APA-seq), PQBP1 knockdown/KO, CFIm complex co-immunoprecipitation, in vitro binding assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CLIP-seq direct binding, multi-omics, co-IP, functional phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"39037895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The PQBP1 Y65C missense mutation causes PQBP1 misfolding and reduced protein levels (partial loss-of-function), impairing apical progenitor proliferation and microcephaly in knock-in mice. Additionally, Y65C causes a gain-of-function by enhancing interactions with core components of the mRNA 3' end processing machinery, preserving proliferative alternative polyadenylation profiles that interfere with the apical-to-basal progenitor transition.\",\n      \"method\": \"Pqbp1-Y65C knock-in mice, brain progenitor cell analysis (IHC, EdU labeling), co-immunoprecipitation (Y65C mutant with 3' end processing machinery), APA profiling, protein stability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model, co-IP with disease mutant, APA profiling, multiple cellular phenotype readouts; multiple orthogonal methods\",\n      \"pmids\": [\"41507200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PQBP1 overexpression induces nuclear inclusions whose formation is dramatically enhanced by co-expression of the pre-mRNA splicing factor SIPP1. Site-directed mutagenesis shows that multiple independent interaction sites between SIPP1 and PQBP1 are required for inclusion facilitation. The inclusions are highly dynamic, do not colocalize with known nuclear structures, and their formation does not require energy.\",\n      \"method\": \"Transfection/overexpression, immunofluorescence, site-directed mutagenesis, FRAP (fluorescence recovery after photobleaching)\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mutagenesis of interaction sites, FRAP, immunofluorescence; single lab\",\n      \"pmids\": [\"18599155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PQBP1 knockdown in mice impairs anxiety-related cognition and reduces c-fos upregulation and histone H3 acetylation in amygdala, prefrontal cortex, and hippocampus after behavioral tests. The HDAC inhibitor 4-phenylbutyric acid rescues gene expression and behavioral phenotypes, linking PQBP1 to chromatin-dependent gene expression in cognitive circuits.\",\n      \"method\": \"Transgenic siRNA knockdown mouse, behavioral tests (open field, EPM, novel object recognition), immunohistochemistry (c-fos, H3 acetylation), pharmacological rescue (HDAC inhibitor)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD mouse model, behavioral and molecular phenotype, pharmacological rescue; single lab\",\n      \"pmids\": [\"19661183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Frameshift PQBP-1 mutants K192Sfs*7 and R153Sfs*41 form stable dimers (unlike monomeric wild-type), have more folded content and higher thermal stability, and show significantly weakened binding to phosphorylated RNA Pol II CTD heptapeptide (YpSPTpSPS), suggesting their toxicity arises from loss of transcriptional regulatory function rather than aggregation.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), biophysical characterization, fluorescence anisotropy binding assay with labeled Pol II CTD peptide\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biophysical characterization and binding assay, single lab, single paper\",\n      \"pmids\": [\"30951824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"High-fat diet (HFD) suppresses PPARγ-mediated transcriptional expression of PQBP1, leading to alternative splicing changes in synapse-related genes (CASK, Cacnb1, Cyfip2, Syt1) that impair presynaptic vesicle release and cognitive function. AAV-PQBP1 or AAVs expressing individual target genes rescue synapse and cognitive dysfunctions in HFD mice.\",\n      \"method\": \"RNA-seq (alternative splicing), chromatin assays, primary neuron electrophysiology/vesicle release assay, AAV rescue in vivo, immunohistochemistry\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq, functional vesicle release assay, in vivo AAV rescue; preprint, single lab\",\n      \"pmids\": [\"40502014\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PQBP1 is a multifunctional nuclear-cytoplasmic protein that (1) regulates pre-mRNA alternative splicing and alternative polyadenylation by associating with spliceosomal components (U5-15kD via a YxxPxxVL motif, SF3B1, WBP11/SIPP1, TXNL4A) and by blocking CFIm complex recruitment to UGUA elements; (2) in the cytoplasm, binds non-phosphorylated eEF2 to suppress eEF2K-mediated Thr56 phosphorylation, promoting translational elongation and mGluR-LTD; (3) acts as an innate immune sensor by decorating intact HIV-1 capsids (via N-terminal acidic residues contacting the CA hexamer arginine ring), recruiting cGAS at the site of reverse transcription to initiate an IRF3-dependent interferon response, and by directly binding exogenous tau to activate cGAS-STING-NFκB-driven microglial inflammation; (4) inhibits transcriptional activation (e.g., by Brn-2 and RNA Pol II) and, when bound by expanded-polyglutamine proteins such as mutant ataxin-1, is redirected to the Pol II C-terminal domain, suppressing transcription and triggering apoptosis; and (5) interacts with Dynamin 2 to inhibit its GTPase activity and promote neuronal ciliogenesis, with XLID-causing WW domain mutations disrupting this function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PQBP1 is a multifunctional polar-amino-acid- and WW-domain-containing protein that operates in both the nucleus and cytoplasm to couple RNA processing, translational control, and innate immune sensing to neuronal development and survival [#0, #5]. In the nucleus it acts as an alternative-splicing and alternative-polyadenylation effector: it binds spliceosomal factors including the U2 snRNP component SF3B1, WBP11/SIPP1, and the U5-15kD protein, with the C-terminal YxxPxxVL motif docking into the U5-15kD hydrophobic groove, and its loss reshapes splicing of target transcripts and impairs dendritic and neurite outgrowth [#3, #5, #7, #25]. PQBP1 binds exonic regions of pre-mRNAs directly and also engages upstream UGUA elements to block CFIm recruitment, thereby controlling poly(A)-site selection in cell-cycle and progenitor genes; through these activities it governs splicing decisions such as Numb exon 9 inclusion and BAX exon 2 skipping that set the balance between progenitor proliferation and differentiation or apoptosis [#22, #23, #24]. It additionally chaperones nuclear import of the splicing factor TXNL4A by a karyopherin-β2 piggyback mechanism [#15]. In the cytoplasm PQBP1 binds non-phosphorylated eEF2 to suppress eEF2K-mediated Thr56 phosphorylation, promoting translational elongation and hippocampal mGluR-dependent long-term depression, and partners with FMRP/dFMR1 in neuronal RNA granules to control translation of specific mRNAs [#11, #17]. PQBP1 also serves as an innate immune sensor that decorates intact HIV-1 capsids—through charge-complementing contacts between its N-terminal acidic residues and the arginine ring of the CA hexamer—and recruits cGAS to drive an IRF3-dependent interferon response, and it directly binds extracellular tau to activate cGAS-STING-NFκB-driven microglial inflammation [#10, #16, #19, #20]. Finally, PQBP1 binds polyglutamine tracts and represses transcription, an activity hijacked by expanded-polyglutamine ataxin-1 that redirects PQBP1 to the RNA Pol II C-terminal domain to suppress transcription and trigger apoptosis [#0, #1]. PQBP1 mutations cause X-linked intellectual disability syndromes (Golabi-Ito-Hall and Renpenning), where loss of splicing-factor and ligand binding, mislocalization of partners, or gain-of-function gains of new binding surfaces produce microcephaly and neuronal dysfunction [#3, #7, #15, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established PQBP1 as a nuclear polyglutamine-binding protein that represses transcription, defining its founding activity and domain architecture.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, transcription reporter and viability assays\",\n      \"pmids\": [\"10332029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define direct transcriptional mechanism\", \"Physiological splicing role not yet known\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that expanded-polyglutamine ataxin-1 enhances PQBP1 binding to the Pol II CTD, reducing CTD phosphorylation and inducing apoptosis, linking PQBP1 to polyQ disease pathology.\",\n      \"evidence\": \"Co-immunoprecipitation, transcription and apoptosis assays in cell lines\",\n      \"pmids\": [\"12062018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether this mechanism operates in neurons in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that excess PQBP1 alone causes progressive neurodegeneration in mice, showing dosage sensitivity of PQBP1 activity.\",\n      \"evidence\": \"Transgenic mouse overexpression with histopathology\",\n      \"pmids\": [\"12651867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of toxicity not resolved\", \"Single lab, ubiquitous overexpression\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified SIPP1/WBP11 as a PQBP1 partner driving dynamic nuclear inclusion formation, pointing toward a splicing-related nuclear function.\",\n      \"evidence\": \"Overexpression, immunofluorescence, site-directed mutagenesis, FRAP\",\n      \"pmids\": [\"18599155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of inclusions unknown\", \"Relationship to physiological splicing unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked PQBP1 to cognition by showing knockdown impairs anxiety-related behavior and chromatin-associated gene induction, rescued by an HDAC inhibitor.\",\n      \"evidence\": \"siRNA knockdown mouse, behavioral tests, IHC, pharmacological rescue\",\n      \"pmids\": [\"19661183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin mechanism not defined\", \"Connection to splicing function not made\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected a WW-domain disease mutation (Y65C, Golabi-Ito-Hall) to loss of proline-rich ligand binding and reduced splicing efficiency, establishing splicing dysfunction as a disease mechanism.\",\n      \"evidence\": \"In vitro binding with mutagenesis, patient lymphoblast co-IP, RT-PCR splicing assay\",\n      \"pmids\": [\"20410308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide splicing targets not yet mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a cytoplasmic PQBP1 pool in RNA-dependent complexes with FMRP and RNA-binding/transport proteins, including stress-granule association, expanding its role beyond the nucleus.\",\n      \"evidence\": \"Co-IP, immunofluorescence, RNase-dependency, stress-granule induction\",\n      \"pmids\": [\"21933836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mRNA targets of cytoplasmic complexes undefined\", \"Functional consequence of SG association unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined PQBP1 as a genome-wide alternative-splicing effector acting through SF3B1, and showed disease mutants fail to support neurite outgrowth, unifying its biochemistry with neuronal phenotype.\",\n      \"evidence\": \"MS interactome, RIP, RNA-seq, neuronal knockdown, mutant complementation\",\n      \"pmids\": [\"23512658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding specificity not yet mapped at nucleotide resolution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a non-splicing cytoplasmic role: PQBP1 inhibits Dynamin 2 GTPase to promote neuronal ciliogenesis, with a WW-domain XLID mutation disrupting this function.\",\n      \"evidence\": \"Localization, in vivo cortical knockdown, co-IP, GTPase assay, epistasis, mutant analysis\",\n      \"pmids\": [\"23994472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of the Dynamin 2 interaction not defined\", \"Relationship to splicing role not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structure of the PQBP1–U5-15kD complex defined the YxxPxxVL recognition motif and explained why frameshift XLID mutations that delete this motif are pathogenic.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, binding assay\",\n      \"pmids\": [\"24781215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how WW-domain partners influence this interaction\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PQBP1 loss causes microcephaly by lengthening NSPC M phase via APC gene dysregulation, with Apc4 and in utero AAV-PQBP1 rescuing the phenotype, connecting splicing/transcription control to brain size.\",\n      \"evidence\": \"Conditional KO mouse, cell-cycle imaging, expression profiling, genetic and gene-therapy rescue\",\n      \"pmids\": [\"25070536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APC effects are direct splicing targets not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated developmental specificity by showing PQBP1 controls FGFR2 alternative splicing and FGF target induction in Xenopus, with WBP11 as a partner.\",\n      \"evidence\": \"Morpholino knockdown, RT-PCR splicing, animal cap assays, in situ hybridization\",\n      \"pmids\": [\"25209246\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian conservation of FGFR2 regulation untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PQBP1 as an innate immune sensor that binds reverse-transcribed HIV-1 DNA and recruits cGAS for an IRF3 response, with patient cells showing attenuated immunity.\",\n      \"evidence\": \"RNAi screen in primary MDDCs, DNA binding, cGAS co-IP, IRF3 assay, patient cell validation\",\n      \"pmids\": [\"26046437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initial step of viral recognition not yet defined\", \"How PQBP1 reaches viral DNA unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a conserved cytoplasmic translational role: PQBP1/dPQBP1 partners with FMRP to control translation of specific mRNAs such as Chaoptin, required for photoreceptor morphogenesis.\",\n      \"evidence\": \"Co-IP, polysome fractionation, Drosophila KO and rescue\",\n      \"pmids\": [\"26002102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of mRNA selection undefined\", \"Drosophila ortholog model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed negative allosteric coupling between PQBP1's WW domain (WBP11) and C-terminal (U5-15kD) interfaces, showing the two RNA-processing partnerships are mutually regulated.\",\n      \"evidence\": \"SPR, pulldown, NMR\",\n      \"pmids\": [\"27314904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the allostery untested\", \"Single biophysical study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed specific frameshift mutations create a new epitope that binds and degrades non-phosphorylated FMRP, defining a gain-of-function disease mechanism affecting synaptic scaling.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, synaptic scaling, Drosophila NMJ rescue\",\n      \"pmids\": [\"28073926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all frameshift mutations act this way unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PQBP1 downstream of SRRM2 stability and linked PQBP1 loss to synapse-gene mis-splicing in Alzheimer's models, with AAV-PQBP1 rescuing cognition.\",\n      \"evidence\": \"Phosphoproteomics, conditional KO, RNA-seq, co-IP, AAV rescue in AD models\",\n      \"pmids\": [\"30283027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PQBP1 binding to affected transcripts not all mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed XLID frameshift mutants form stable dimers and lose binding to phosphorylated Pol II CTD, arguing toxicity arises from loss of transcriptional regulation rather than aggregation.\",\n      \"evidence\": \"SAXS, biophysical characterization, fluorescence anisotropy CTD binding\",\n      \"pmids\": [\"30951824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular consequence of dimerization untested\", \"Single in vitro study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined PQBP1 as a nuclear-import chaperone for TXNL4A via karyopherin-β2 piggyback, with the P244L XLID mutation disrupting this transport.\",\n      \"evidence\": \"Recombinant binding assays, immunofluorescence, disease-mutant analysis\",\n      \"pmids\": [\"32041777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether import defect drives disease phenotypes in vivo not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a direct translational-elongation mechanism: PQBP1 binds non-phosphorylated eEF2 to block eEF2K phosphorylation, promoting elongation and mGluR-LTD.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, puromycin labeling, mGluR-LTD electrophysiology, KO\",\n      \"pmids\": [\"33662272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear and cytoplasmic functions are partitioned unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended PQBP1 immune sensing to neurodegeneration by showing it directly binds extracellular tau to drive cGAS-STING-NFκB microglial inflammation, with microglial depletion preventing cognitive impairment.\",\n      \"evidence\": \"Direct binding, cGAS-STING readouts, microglia-specific inducible KO, cognition tests\",\n      \"pmids\": [\"34782623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of tau recognition undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified LATS2 as a kinase partner enhancing PQBP1-dependent cGAS-STING responses to HIV-1, independent of canonical Hippo YAP/TAZ signaling.\",\n      \"evidence\": \"Co-IP, kinase assay, interferon reporter, HIV-1 infection\",\n      \"pmids\": [\"34385679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PQBP1 phosphorylation site not fully validated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that PQBP1 decorates the intact HIV-1 capsid as the primary recognition event upstream of cGAS recruitment, resolving how cGAS reaches viral DNA.\",\n      \"evidence\": \"Proximity ligation, co-IP, capsid binding, imaging time-course\",\n      \"pmids\": [\"35809572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of capsid contact not yet defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural basis for capsid recognition, mapping N-terminal acidic residues of PQBP1 to the arginine ring of the CA hexamer central channel.\",\n      \"evidence\": \"Structural analysis of CA hexamer, mutagenesis, in vitro capsid binding\",\n      \"pmids\": [\"38128824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How capsid binding triggers cGAS conformational activation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed PQBP1 promotes Numb exon 9 inclusion to maintain striatal progenitor proliferation, linking a defined splicing event to neurodevelopmental outcome.\",\n      \"evidence\": \"Striatum-specific conditional KO, RNA-seq, RT-PCR, proliferation assays, histology\",\n      \"pmids\": [\"36943865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Numb mis-splicing alone explains the phenotype untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated PQBP1 binds exonic pre-mRNA regions and drives BAX exon 2 skipping to evade apoptosis, defining a pro-tumorigenic splicing role and an ASO therapeutic strategy.\",\n      \"evidence\": \"spyCLIP-seq, RNA-seq, knockdown/overexpression, ASO rescue, xenograft\",\n      \"pmids\": [\"38342602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across cancer types not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a new RNA-processing axis: PQBP1 binds UGUA elements and blocks CFIm recruitment to control alternative polyadenylation in cell-cycle genes governing NPC fate.\",\n      \"evidence\": \"CLIP-seq, RNA-seq, APA-seq, CFIm co-IP, in vitro binding, knockdown/KO\",\n      \"pmids\": [\"39037895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How splicing and APA functions are coordinated unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved that the Y65C mutation combines partial loss-of-function (misfolding, reduced levels) with gain-of-function enhanced binding to 3'-end processing machinery, distorting APA profiles and progenitor transitions.\",\n      \"evidence\": \"Y65C knock-in mice, progenitor analysis, mutant co-IP, APA profiling, stability assays\",\n      \"pmids\": [\"41507200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of loss vs gain to human disease severity unquantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PQBP1's distinct nuclear (splicing/APA/transcription), cytoplasmic (translation), and immune-sensing activities are partitioned and coordinated within a single neuron, and which are decisive for each XLID phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model partitioning the functions by compartment or stimulus\", \"Which activity dominates in each disease context is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [22, 23, 5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10, 16, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 17]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [16, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 23, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 16, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 21, 6]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 23]}\n    ],\n    \"complexes\": [\"spliceosome (SF3B1/U5-15kD-associated)\"],\n    \"partners\": [\"SF3B1\", \"WBP11\", \"TXNL4A\", \"cGAS\", \"eEF2\", \"DNM2\", \"FMRP\", \"LATS2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}