{"gene":"IPO7","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"RanBP7 (IPO7) directly binds and imports ribosomal proteins (rpL23a, rpS7, rpL5) into the nucleus in mammalian cells, acting as one of at least four importin beta-like transport receptors for this function. The binding occurs at a very basic region of rpL23a that serves as an archetypal import signal.","method":"In vitro nuclear import assay, direct binding (pulldown), competition experiments with ribosomal proteins and import receptors","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted nuclear import assay with direct binding experiments; replicated across multiple substrates and receptors in a rigorous biochemical study","pmids":["9687515"],"is_preprint":false},{"year":2015,"finding":"IPO7 (Imp7) mediates nuclear translocation of the Smad2/3/4 complex in TGF-β1-stimulated myofibroblasts. MAPK-specific inhibitors (ERK, JNK, p38) block Smad2/3/4 nuclear translocation by reducing Imp7/8 expression, demonstrating that Imp7 is required for this nuclear import step in TGF-β/Smad signaling.","method":"Subcellular fractionation, western blot for nuclear vs. cytoplasmic distribution, pharmacological inhibition of MAPK pathways, protein and mRNA expression analysis","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (PAI-1 expression), single lab, two orthogonal methods (protein fractionation + mRNA); Imp7 and Imp8 not distinguished individually","pmids":["25968067"],"is_preprint":false},{"year":2021,"finding":"IPO7 is an essential gene in at least three cell lines, as demonstrated by CRISPR-Cas9 knockout being lethal; increasing IPO7 expression levels inhibits cell growth. EBV miRNAs target IPO7 mRNA to limit its accumulation, tuning host cell survival during infection.","method":"CRISPR-Cas9 mutagenesis (loss-of-function), overexpression of IPO7 with growth assay","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype (essentiality) across three cell lines; single lab but orthogonal KO and OE approaches","pmids":["33664726"],"is_preprint":false},{"year":2022,"finding":"IPO7 promotes odontoblastic differentiation and inhibits osteoblastic differentiation through distinct mechanisms: in dental papilla cells, IPO7 binds odontoblastic transcription factors and imports them into the nucleus, and inhibits total RUNX2 expression by promoting HDAC6 nuclear localization; in osteoblasts (MC3T3-E1), IPO7 inhibits RUNX2 nuclear distribution without affecting total RUNX2 protein levels.","method":"Co-immunoprecipitation (binding of IPO7 with transcription factors), knockdown (siRNA/shRNA) with differentiation assays, western blot for nuclear vs. total protein fractionation, overexpression experiments","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for binding partners, KD/OE with defined differentiation phenotypes, subcellular fractionation; single lab with multiple orthogonal methods","pmids":["35922041"],"is_preprint":false},{"year":2023,"finding":"IPO7 interacts with phospho-p38 (p-p38) under LPS stimulation in human dental pulp cells and mediates nuclear translocation of p-p38, thereby promoting NF-κB and p38 MAPK signaling and inflammatory cytokine production. Knockdown of IPO7 inhibits this pathway; increased IPO7–p-p38 binding is associated with decreased IPO7–Sirt2 binding.","method":"Co-immunoprecipitation (IPO7 with p-p38 and Sirt2), siRNA knockdown, pathway activator rescue experiments, western blot","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, KD with rescue by activators, single lab with multiple orthogonal approaches","pmids":["37769576"],"is_preprint":false},{"year":2024,"finding":"IPO7 (Imp7) is required for HMGB1 secretion/release; Imp7 siRNA nanoparticles inhibit HMGB1 production in a mouse model of ventilator-induced lung injury, thereby preventing neutrophil extracellular trap (NET) formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway.","method":"SiRNA knockdown in vivo (nanoparticle delivery), ELISA, histological assessment of liver injury, mechanistic pathway analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined molecular phenotype (HMGB1 secretion, NETs, PANoptosis); single lab, pathway mechanistically placed","pmids":["38369216"],"is_preprint":false},{"year":2025,"finding":"IPO7 associates with the Golgi apparatus and is required for HPV transport from the Golgi to the nucleus during infection. The C-terminus of HPV capsid protein L2 directly binds IPO7 in a step dependent on prior COPI-mediated virus trafficking. Knockdown of IPO7 traps HPV in the Golgi and prevents nuclear entry.","method":"IPO7 knockdown (HPV infection inhibition assay), subcellular localization (Golgi association), direct binding (pulldown of L2 C-terminus with IPO7), COPI inhibition epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pulldown establishing L2-IPO7 interaction, KD with defined localization phenotype, epistasis with COPI pathway; single lab, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.01.08.631933"],"is_preprint":true},{"year":2025,"finding":"The Impβ/IPO7 heterodimer interaction is mediated by a short C-terminal nucleoporin-like binding (NlB) region of IPO7 that contacts the outer surface of Impβ via FXFG nucleoporin motifs, and Impβ allosterically activates IPO7. Only the preassembled Impβ/IPO7 heterodimer (not either importin alone) enables proper binding of the H1 globular domain—positioned within the central cavity of IPO7—for nuclear translocation. The model was validated by cross-linking mass spectrometry, ITC, and pulldown against a cryo-EM map.","method":"AlphaFold3 structural prediction validated by cross-linking/mass spectrometry, isothermal titration calorimetry (ITC), pulldown experiments, and cryo-EM map refinement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural model with multiple orthogonal biophysical validations (XL-MS, ITC, pulldown, cryo-EM); single lab, preprint not yet peer-reviewed lowers confidence from High","pmids":["bio_10.1101_2025.08.04.668392"],"is_preprint":true},{"year":2021,"finding":"IPO7 knockdown in pancreatic cancer cells suppresses p53 expression and induces MALAT1 lncRNA expression while reducing miR-129-5p; miR-129-5p post-transcriptionally regulates IPO7 (validated by luciferase reporter and RIP/pulldown), forming a positive feedback loop that promotes pancreatic cancer progression.","method":"siRNA knockdown, western blot, dual-luciferase reporter, RNA immunoprecipitation (RIP), pulldown assay, xenograft mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — multiple methods used, but mechanistic placement of IPO7 in the p53/MALAT1 axis relies on indirect correlative readouts; no direct biochemical interaction between IPO7 and p53 established; single lab","pmids":["34660566"],"is_preprint":false}],"current_model":"IPO7 (RanBP7/Imp7) is an importin-β family nuclear transport receptor that directly imports ribosomal proteins and histone H1 (as an obligate Impβ/IPO7 heterodimer with H1 docking in IPO7's central cavity) through the nuclear pore; it additionally mediates nuclear import of phospho-p38 MAPK and Smad2/3/4 complexes to modulate inflammatory and TGF-β signaling, promotes HDAC6 and odontoblastic transcription factor nuclear localization to regulate cell differentiation, is required for HMGB1 secretion during inflammatory injury, and is exploited by HPV via direct L2 capsid protein binding at the Golgi for nuclear entry."},"narrative":{"mechanistic_narrative":"IPO7 (RanBP7/Imp7) is an importin-β family nuclear transport receptor that recognizes basic import signals on cargo proteins and delivers them across the nuclear pore [PMID:9687515]. It was first defined as one of several importin-β-like receptors that directly bind and import ribosomal proteins (rpL23a, rpS7, rpL5), recognizing an archetypal basic import signal [PMID:9687515]. Structurally, IPO7 functions with importin-β as a preassembled heterodimer: a short C-terminal nucleoporin-like binding region of IPO7 contacts importin-β through FXFG-type motifs, importin-β allosterically activates IPO7, and only the assembled heterodimer can dock the histone H1 globular domain within IPO7's central cavity for translocation [PMID:bio_10.1101_2025.08.04.668392]. Beyond constitutive cargo, IPO7 serves as the nuclear import step for multiple signaling effectors: it mediates nuclear translocation of the Smad2/3/4 complex in TGF-β-stimulated myofibroblasts [PMID:25968067] and of phospho-p38 under inflammatory (LPS) stimulation, thereby driving NF-κB/p38 MAPK signaling and cytokine production, with IPO7–p-p38 binding inversely related to IPO7–Sirt2 binding [PMID:37769576]. In dental papilla cells IPO7 binds odontoblastic transcription factors to import them and promotes HDAC6 nuclear localization, coupling its transport activity to control of odontoblastic versus osteoblastic differentiation through effects on RUNX2 [PMID:35922041]. IPO7 is also required for HMGB1 release during inflammatory lung injury, linking it to downstream NET formation and PANoptosis [PMID:38369216], and is exploited by HPV, whose L2 capsid C-terminus directly binds Golgi-associated IPO7 for nuclear entry following COPI-dependent trafficking [PMID:bio_10.1101_2025.01.08.631933]. IPO7 is essential for viability in multiple cell lines [PMID:33664726].","teleology":[{"year":1998,"claim":"Established IPO7's foundational activity as a nuclear import receptor by showing it directly binds and imports ribosomal proteins, defining its substrate-recognition mode through a basic import signal.","evidence":"In vitro reconstituted nuclear import assay with direct binding and competition experiments using multiple ribosomal protein substrates","pmids":["9687515"],"confidence":"High","gaps":["Did not resolve the structural basis of cargo recognition","Did not address signaling-effector cargoes or heterodimer requirement"]},{"year":2015,"claim":"Placed IPO7 in TGF-β signaling by identifying it as the import carrier required for Smad2/3/4 nuclear translocation, connecting receptor-level kinase activity to transcriptional output.","evidence":"Subcellular fractionation, MAPK pharmacological inhibition, and protein/mRNA expression analysis in TGF-β1-stimulated myofibroblasts","pmids":["25968067"],"confidence":"Medium","gaps":["Imp7 and Imp8 contributions not individually distinguished","No direct binding between IPO7 and Smad complex demonstrated"]},{"year":2021,"claim":"Defined IPO7 as an essential gene and a target of viral regulation, showing its dosage is tightly constrained and tuned by EBV miRNAs during infection.","evidence":"CRISPR-Cas9 knockout (lethal) and overexpression growth assays across three cell lines","pmids":["33664726"],"confidence":"Medium","gaps":["Molecular basis of essentiality (which cargoes) not identified","Mechanism by which overexpression inhibits growth unresolved"]},{"year":2022,"claim":"Linked IPO7's transport function to cell-fate control by showing it imports odontoblastic transcription factors and HDAC6 to bias differentiation toward odontoblastic over osteoblastic programs via RUNX2.","evidence":"Reciprocal Co-IP, knockdown/overexpression with differentiation assays, and nuclear-versus-total fractionation","pmids":["35922041"],"confidence":"Medium","gaps":["Specific transcription-factor cargoes only partially identified","Single lab; differentiation phenotype not independently replicated"]},{"year":2023,"claim":"Extended IPO7's role to inflammatory signaling by identifying phospho-p38 as a direct interactor whose nuclear import drives NF-κB/p38 cytokine responses, with Sirt2 as a competing partner.","evidence":"Co-IP of IPO7 with p-p38 and Sirt2, siRNA knockdown, and pathway-activator rescue in dental pulp cells","pmids":["37769576"],"confidence":"Medium","gaps":["Functional consequence of the IPO7–Sirt2 interaction not directly tested","Whether IPO7 imports other MAPK components unaddressed"]},{"year":2024,"claim":"Implicated IPO7 in inflammatory injury physiology by showing it is required for HMGB1 secretion, connecting its activity to downstream NET formation and PANoptosis in vivo.","evidence":"In vivo siRNA-nanoparticle knockdown in ventilator-induced lung injury, ELISA, and histological injury assessment","pmids":["38369216"],"confidence":"Medium","gaps":["Direct mechanism by which IPO7 controls HMGB1 release not defined","Whether effect is via nuclear import of an upstream factor unclear"]},{"year":2025,"claim":"Revealed a viral hijacking mechanism in which Golgi-associated IPO7 is the receptor for HPV nuclear entry through direct binding of the L2 capsid C-terminus after COPI-dependent trafficking.","evidence":"IPO7 knockdown HPV infection assay, Golgi localization, L2 C-terminus pulldown, and COPI inhibition epistasis (preprint)","pmids":["bio_10.1101_2025.01.08.631933"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How Golgi-localized IPO7 transits the virus to the pore unresolved"]},{"year":2025,"claim":"Provided the structural logic for IPO7 cargo handling, showing it functions as an importin-β heterodimer whose central cavity docks histone H1 only after importin-β allosterically activates it via a C-terminal nucleoporin-like region.","evidence":"AlphaFold3 model validated by cross-linking mass spectrometry, ITC, pulldown, and cryo-EM map refinement (preprint)","pmids":["bio_10.1101_2025.08.04.668392"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Whether the heterodimer requirement generalizes to other cargoes untested"]},{"year":null,"claim":"It remains unresolved how IPO7 selects among its diverse cargoes (ribosomal proteins, H1, Smad complexes, p-p38, transcription factors, viral L2) and whether shared structural determinants govern monomeric versus heterodimeric import.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified cargo-selectivity model across constitutive and signaling substrates","Regulation of monomer-versus-heterodimer assembly in cells unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,4,7]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5]}],"complexes":["Importin-β/IPO7 heterodimer"],"partners":["IPOB (IMPORTIN-BETA)","SMAD2","SMAD3","SMAD4","MAPK14 (P38)","SIRT2","HDAC6","HMGB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95373","full_name":"Importin-7","aliases":["Ran-binding protein 7","RanBP7"],"length_aa":1038,"mass_kda":119.5,"function":"Functions in nuclear protein import, either by acting as autonomous nuclear transport receptor or as an adapter-like protein in association with the importin-beta subunit KPNB1. Acting autonomously, is thought to serve itself as receptor for nuclear localization signals (NLS) and to promote translocation of import substrates through the nuclear pore complex (NPC) by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5 (PubMed:11682607). In association with KPNB1 mediates the nuclear import of H1 histone and the Ran-binding site of IPO7 is not required but synergizes with that of KPNB1 in importin/substrate complex dissociation. Promotes odontoblast differentiation via promoting nuclear translocation of DLX3, KLF4, SMAD2, thereby facilitating the transcription of target genes that play a role in odontoblast differentiation (By similarity). Facilitates BMP4-induced translocation of SMAD1 to the nucleus and recruitment to the MSX1 gene promoter, thereby promotes the expression of the odontogenic regulator MSX1 in dental mesenchymal cells (By similarity). Also promotes odontoblast differentiation by facilitating the nuclear translocation of HDAC6 and subsequent repression of RUNX2 expression (By similarity). Inhibits osteoblast differentiation by inhibiting nuclear translocation of RUNX2 and therefore inhibition of RUNX2 target gene transcription (By similarity). In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones (Microbial infection) Mediates the nuclear import of HIV-1 reverse transcription complex (RTC) integrase. Binds and mediates the nuclear import of HIV-1 Rev","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O95373/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IPO7","classification":"Common Essential","n_dependent_lines":1186,"n_total_lines":1208,"dependency_fraction":0.9817880794701986},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000205339","cell_line_id":"CID001555","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"KPNB1","stoichiometry":10.0},{"gene":"H1F0","stoichiometry":4.0},{"gene":"TRIM28","stoichiometry":4.0},{"gene":"H1FX","stoichiometry":4.0},{"gene":"NAP1L4","stoichiometry":4.0},{"gene":"ATP6V1F","stoichiometry":0.2},{"gene":"CDX2","stoichiometry":0.2},{"gene":"HP1BP3","stoichiometry":0.2},{"gene":"NAP1L1","stoichiometry":0.2},{"gene":"SAFB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001555","total_profiled":1310},"omim":[{"mim_id":"614351","title":"NUCLEOPORIN, 93-KD; NUP93","url":"https://www.omim.org/entry/614351"},{"mim_id":"605586","title":"IMPORTIN 7; IPO7","url":"https://www.omim.org/entry/605586"},{"mim_id":"176948","title":"MITOGEN-ACTIVATED PROTEIN KINASE 1; MAPK1","url":"https://www.omim.org/entry/176948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IPO7"},"hgnc":{"alias_symbol":["Imp7"],"prev_symbol":["RANBP7"]},"alphafold":{"accession":"O95373","domains":[{"cath_id":"1.25.10","chopping":"344-535","consensus_level":"medium","plddt":93.6294,"start":344,"end":535},{"cath_id":"-","chopping":"835-881_945-1008","consensus_level":"medium","plddt":88.3998,"start":835,"end":1008}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95373","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95373-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95373-F1-predicted_aligned_error_v6.png","plddt_mean":87.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IPO7","jax_strain_url":"https://www.jax.org/strain/search?query=IPO7"},"sequence":{"accession":"O95373","fasta_url":"https://rest.uniprot.org/uniprotkb/O95373.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95373/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95373"}},"corpus_meta":[{"pmid":"9687515","id":"PMC_9687515","title":"Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9687515","citation_count":432,"is_preprint":false},{"pmid":"22815235","id":"PMC_22815235","title":"Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22815235","citation_count":65,"is_preprint":false},{"pmid":"28993328","id":"PMC_28993328","title":"Molecular Characterization of Carbapenemase-Producing Pseudomonas aeruginosa of Czech Origin and Evidence for Clonal Spread of Extensively Resistant Sequence Type 357 Expressing IMP-7 Metallo-β-Lactamase.","date":"2017","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/28993328","citation_count":48,"is_preprint":false},{"pmid":"30045750","id":"PMC_30045750","title":"SWATH-MS based quantitative proteomics analysis reveals that curcumin alters the metabolic enzyme profile of CML cells by affecting the activity of miR-22/IPO7/HIF-1α axis.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30045750","citation_count":41,"is_preprint":false},{"pmid":"10799331","id":"PMC_10799331","title":"Elevated levels of RanBP7 mRNA in colorectal carcinoma are associated with increased proliferation and are similar to the transcription pattern of the proto-oncogene c-myc.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10799331","citation_count":26,"is_preprint":false},{"pmid":"12234862","id":"PMC_12234862","title":"Carbapenem-resistant Pseudomonas aeruginosa in malaysia producing IMP-7 beta-lactamase.","date":"2002","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/12234862","citation_count":25,"is_preprint":false},{"pmid":"34660566","id":"PMC_34660566","title":"Pancreatic Cancer Progression Is Regulated by IPO7/p53/LncRNA MALAT1/MiR-129-5p Positive Feedback Loop.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34660566","citation_count":23,"is_preprint":false},{"pmid":"20462725","id":"PMC_20462725","title":"Metallo-beta-lactamase-producing imipenem-resistant Pseudomonas aeruginosa clinical isolates in a university teaching hospital in Malaysia: detection of IMP-7 and first identification of IMP-4, VIM-2, and VIM-11.","date":"2010","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/20462725","citation_count":17,"is_preprint":false},{"pmid":"25968067","id":"PMC_25968067","title":"MAPK inhibitors modulate Smad2/3/4 complex cyto-nuclear translocation in myofibroblasts via Imp7/8 mediation.","date":"2015","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25968067","citation_count":14,"is_preprint":false},{"pmid":"38369216","id":"PMC_38369216","title":"Imp7 siRNA nanoparticles protect against mechanical ventilation-associated liver injury by inhibiting HMGB1 production and NETs formation.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38369216","citation_count":13,"is_preprint":false},{"pmid":"30112050","id":"PMC_30112050","title":"Compound Astragalus and Salvia miltiorrhiza extract inhibits hepatocarcinogenesis via modulating TGF-β/TβR and Imp7/8.","date":"2018","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30112050","citation_count":12,"is_preprint":false},{"pmid":"37516020","id":"PMC_37516020","title":"Systemic cytokines inhibition with Imp7 siRNA nanoparticle ameliorates gut injury in a mouse model of ventilator-induced lung injury.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37516020","citation_count":11,"is_preprint":false},{"pmid":"35922041","id":"PMC_35922041","title":"IPO7 Promotes Odontoblastic Differentiation and Inhibits Osteoblastic Differentiation Through Regulation of RUNX2 Expression and Translocation.","date":"2022","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/35922041","citation_count":6,"is_preprint":false},{"pmid":"35588577","id":"PMC_35588577","title":"IPO7 promotes pancreatic cancer progression via regulating ERBB pathway.","date":"2022","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/35588577","citation_count":5,"is_preprint":false},{"pmid":"37769576","id":"PMC_37769576","title":"IPO7 promotes lipopolysaccharide-induced inflammatory responses in human dental pulp cells via p38 MAPK and NF-κB signaling pathways.","date":"2023","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37769576","citation_count":3,"is_preprint":false},{"pmid":"33664726","id":"PMC_33664726","title":"Epstein-Barr Virus Limits the Accumulation of IPO7, an Essential Gene Product.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33664726","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.04.668392","title":"Alphafold 3 guided insights into the Importin β - Importin 7 heterodimer interaction and its binding to Histone H1","date":"2025-08-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.04.668392","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.08.631933","title":"Golgi-associated nuclear import receptor importin-7 targets HPV from the Golgi to the nucleus to promote infection","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.08.631933","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11092,"output_tokens":2633,"usd":0.036386,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9888,"output_tokens":3300,"usd":0.06597,"stage2_stop_reason":"end_turn"},"total_usd":0.102356,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"RanBP7 (IPO7) directly binds and imports ribosomal proteins (rpL23a, rpS7, rpL5) into the nucleus in mammalian cells, acting as one of at least four importin beta-like transport receptors for this function. The binding occurs at a very basic region of rpL23a that serves as an archetypal import signal.\",\n      \"method\": \"In vitro nuclear import assay, direct binding (pulldown), competition experiments with ribosomal proteins and import receptors\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted nuclear import assay with direct binding experiments; replicated across multiple substrates and receptors in a rigorous biochemical study\",\n      \"pmids\": [\"9687515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IPO7 (Imp7) mediates nuclear translocation of the Smad2/3/4 complex in TGF-β1-stimulated myofibroblasts. MAPK-specific inhibitors (ERK, JNK, p38) block Smad2/3/4 nuclear translocation by reducing Imp7/8 expression, demonstrating that Imp7 is required for this nuclear import step in TGF-β/Smad signaling.\",\n      \"method\": \"Subcellular fractionation, western blot for nuclear vs. cytoplasmic distribution, pharmacological inhibition of MAPK pathways, protein and mRNA expression analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (PAI-1 expression), single lab, two orthogonal methods (protein fractionation + mRNA); Imp7 and Imp8 not distinguished individually\",\n      \"pmids\": [\"25968067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IPO7 is an essential gene in at least three cell lines, as demonstrated by CRISPR-Cas9 knockout being lethal; increasing IPO7 expression levels inhibits cell growth. EBV miRNAs target IPO7 mRNA to limit its accumulation, tuning host cell survival during infection.\",\n      \"method\": \"CRISPR-Cas9 mutagenesis (loss-of-function), overexpression of IPO7 with growth assay\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined cellular phenotype (essentiality) across three cell lines; single lab but orthogonal KO and OE approaches\",\n      \"pmids\": [\"33664726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IPO7 promotes odontoblastic differentiation and inhibits osteoblastic differentiation through distinct mechanisms: in dental papilla cells, IPO7 binds odontoblastic transcription factors and imports them into the nucleus, and inhibits total RUNX2 expression by promoting HDAC6 nuclear localization; in osteoblasts (MC3T3-E1), IPO7 inhibits RUNX2 nuclear distribution without affecting total RUNX2 protein levels.\",\n      \"method\": \"Co-immunoprecipitation (binding of IPO7 with transcription factors), knockdown (siRNA/shRNA) with differentiation assays, western blot for nuclear vs. total protein fractionation, overexpression experiments\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for binding partners, KD/OE with defined differentiation phenotypes, subcellular fractionation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35922041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IPO7 interacts with phospho-p38 (p-p38) under LPS stimulation in human dental pulp cells and mediates nuclear translocation of p-p38, thereby promoting NF-κB and p38 MAPK signaling and inflammatory cytokine production. Knockdown of IPO7 inhibits this pathway; increased IPO7–p-p38 binding is associated with decreased IPO7–Sirt2 binding.\",\n      \"method\": \"Co-immunoprecipitation (IPO7 with p-p38 and Sirt2), siRNA knockdown, pathway activator rescue experiments, western blot\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, KD with rescue by activators, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37769576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IPO7 (Imp7) is required for HMGB1 secretion/release; Imp7 siRNA nanoparticles inhibit HMGB1 production in a mouse model of ventilator-induced lung injury, thereby preventing neutrophil extracellular trap (NET) formation and PANoptosis in the liver via the TLR4/MyD88/TRAF6 pathway.\",\n      \"method\": \"SiRNA knockdown in vivo (nanoparticle delivery), ELISA, histological assessment of liver injury, mechanistic pathway analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined molecular phenotype (HMGB1 secretion, NETs, PANoptosis); single lab, pathway mechanistically placed\",\n      \"pmids\": [\"38369216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IPO7 associates with the Golgi apparatus and is required for HPV transport from the Golgi to the nucleus during infection. The C-terminus of HPV capsid protein L2 directly binds IPO7 in a step dependent on prior COPI-mediated virus trafficking. Knockdown of IPO7 traps HPV in the Golgi and prevents nuclear entry.\",\n      \"method\": \"IPO7 knockdown (HPV infection inhibition assay), subcellular localization (Golgi association), direct binding (pulldown of L2 C-terminus with IPO7), COPI inhibition epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pulldown establishing L2-IPO7 interaction, KD with defined localization phenotype, epistasis with COPI pathway; single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.08.631933\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Impβ/IPO7 heterodimer interaction is mediated by a short C-terminal nucleoporin-like binding (NlB) region of IPO7 that contacts the outer surface of Impβ via FXFG nucleoporin motifs, and Impβ allosterically activates IPO7. Only the preassembled Impβ/IPO7 heterodimer (not either importin alone) enables proper binding of the H1 globular domain—positioned within the central cavity of IPO7—for nuclear translocation. The model was validated by cross-linking mass spectrometry, ITC, and pulldown against a cryo-EM map.\",\n      \"method\": \"AlphaFold3 structural prediction validated by cross-linking/mass spectrometry, isothermal titration calorimetry (ITC), pulldown experiments, and cryo-EM map refinement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural model with multiple orthogonal biophysical validations (XL-MS, ITC, pulldown, cryo-EM); single lab, preprint not yet peer-reviewed lowers confidence from High\",\n      \"pmids\": [\"bio_10.1101_2025.08.04.668392\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IPO7 knockdown in pancreatic cancer cells suppresses p53 expression and induces MALAT1 lncRNA expression while reducing miR-129-5p; miR-129-5p post-transcriptionally regulates IPO7 (validated by luciferase reporter and RIP/pulldown), forming a positive feedback loop that promotes pancreatic cancer progression.\",\n      \"method\": \"siRNA knockdown, western blot, dual-luciferase reporter, RNA immunoprecipitation (RIP), pulldown assay, xenograft mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple methods used, but mechanistic placement of IPO7 in the p53/MALAT1 axis relies on indirect correlative readouts; no direct biochemical interaction between IPO7 and p53 established; single lab\",\n      \"pmids\": [\"34660566\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IPO7 (RanBP7/Imp7) is an importin-β family nuclear transport receptor that directly imports ribosomal proteins and histone H1 (as an obligate Impβ/IPO7 heterodimer with H1 docking in IPO7's central cavity) through the nuclear pore; it additionally mediates nuclear import of phospho-p38 MAPK and Smad2/3/4 complexes to modulate inflammatory and TGF-β signaling, promotes HDAC6 and odontoblastic transcription factor nuclear localization to regulate cell differentiation, is required for HMGB1 secretion during inflammatory injury, and is exploited by HPV via direct L2 capsid protein binding at the Golgi for nuclear entry.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IPO7 (RanBP7/Imp7) is an importin-β family nuclear transport receptor that recognizes basic import signals on cargo proteins and delivers them across the nuclear pore [#0]. It was first defined as one of several importin-β-like receptors that directly bind and import ribosomal proteins (rpL23a, rpS7, rpL5), recognizing an archetypal basic import signal [#0]. Structurally, IPO7 functions with importin-β as a preassembled heterodimer: a short C-terminal nucleoporin-like binding region of IPO7 contacts importin-β through FXFG-type motifs, importin-β allosterically activates IPO7, and only the assembled heterodimer can dock the histone H1 globular domain within IPO7's central cavity for translocation [#7]. Beyond constitutive cargo, IPO7 serves as the nuclear import step for multiple signaling effectors: it mediates nuclear translocation of the Smad2/3/4 complex in TGF-β-stimulated myofibroblasts [#1] and of phospho-p38 under inflammatory (LPS) stimulation, thereby driving NF-κB/p38 MAPK signaling and cytokine production, with IPO7–p-p38 binding inversely related to IPO7–Sirt2 binding [#4]. In dental papilla cells IPO7 binds odontoblastic transcription factors to import them and promotes HDAC6 nuclear localization, coupling its transport activity to control of odontoblastic versus osteoblastic differentiation through effects on RUNX2 [#3]. IPO7 is also required for HMGB1 release during inflammatory lung injury, linking it to downstream NET formation and PANoptosis [#5], and is exploited by HPV, whose L2 capsid C-terminus directly binds Golgi-associated IPO7 for nuclear entry following COPI-dependent trafficking [#6]. IPO7 is essential for viability in multiple cell lines [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established IPO7's foundational activity as a nuclear import receptor by showing it directly binds and imports ribosomal proteins, defining its substrate-recognition mode through a basic import signal.\",\n      \"evidence\": \"In vitro reconstituted nuclear import assay with direct binding and competition experiments using multiple ribosomal protein substrates\",\n      \"pmids\": [\"9687515\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the structural basis of cargo recognition\",\n        \"Did not address signaling-effector cargoes or heterodimer requirement\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed IPO7 in TGF-β signaling by identifying it as the import carrier required for Smad2/3/4 nuclear translocation, connecting receptor-level kinase activity to transcriptional output.\",\n      \"evidence\": \"Subcellular fractionation, MAPK pharmacological inhibition, and protein/mRNA expression analysis in TGF-β1-stimulated myofibroblasts\",\n      \"pmids\": [\"25968067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Imp7 and Imp8 contributions not individually distinguished\",\n        \"No direct binding between IPO7 and Smad complex demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined IPO7 as an essential gene and a target of viral regulation, showing its dosage is tightly constrained and tuned by EBV miRNAs during infection.\",\n      \"evidence\": \"CRISPR-Cas9 knockout (lethal) and overexpression growth assays across three cell lines\",\n      \"pmids\": [\"33664726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis of essentiality (which cargoes) not identified\",\n        \"Mechanism by which overexpression inhibits growth unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked IPO7's transport function to cell-fate control by showing it imports odontoblastic transcription factors and HDAC6 to bias differentiation toward odontoblastic over osteoblastic programs via RUNX2.\",\n      \"evidence\": \"Reciprocal Co-IP, knockdown/overexpression with differentiation assays, and nuclear-versus-total fractionation\",\n      \"pmids\": [\"35922041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific transcription-factor cargoes only partially identified\",\n        \"Single lab; differentiation phenotype not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended IPO7's role to inflammatory signaling by identifying phospho-p38 as a direct interactor whose nuclear import drives NF-κB/p38 cytokine responses, with Sirt2 as a competing partner.\",\n      \"evidence\": \"Co-IP of IPO7 with p-p38 and Sirt2, siRNA knockdown, and pathway-activator rescue in dental pulp cells\",\n      \"pmids\": [\"37769576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the IPO7–Sirt2 interaction not directly tested\",\n        \"Whether IPO7 imports other MAPK components unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated IPO7 in inflammatory injury physiology by showing it is required for HMGB1 secretion, connecting its activity to downstream NET formation and PANoptosis in vivo.\",\n      \"evidence\": \"In vivo siRNA-nanoparticle knockdown in ventilator-induced lung injury, ELISA, and histological injury assessment\",\n      \"pmids\": [\"38369216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism by which IPO7 controls HMGB1 release not defined\",\n        \"Whether effect is via nuclear import of an upstream factor unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a viral hijacking mechanism in which Golgi-associated IPO7 is the receptor for HPV nuclear entry through direct binding of the L2 capsid C-terminus after COPI-dependent trafficking.\",\n      \"evidence\": \"IPO7 knockdown HPV infection assay, Golgi localization, L2 C-terminus pulldown, and COPI inhibition epistasis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.08.631933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"How Golgi-localized IPO7 transits the virus to the pore unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural logic for IPO7 cargo handling, showing it functions as an importin-β heterodimer whose central cavity docks histone H1 only after importin-β allosterically activates it via a C-terminal nucleoporin-like region.\",\n      \"evidence\": \"AlphaFold3 model validated by cross-linking mass spectrometry, ITC, pulldown, and cryo-EM map refinement (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.04.668392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed\",\n        \"Whether the heterodimer requirement generalizes to other cargoes untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IPO7 selects among its diverse cargoes (ribosomal proteins, H1, Smad complexes, p-p38, transcription factors, viral L2) and whether shared structural determinants govern monomeric versus heterodimeric import.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unified cargo-selectivity model across constitutive and signaling substrates\",\n        \"Regulation of monomer-versus-heterodimer assembly in cells unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"Importin-β/IPO7 heterodimer\"],\n    \"partners\": [\"IPOB (importin-beta)\", \"SMAD2\", \"SMAD3\", \"SMAD4\", \"MAPK14 (p38)\", \"SIRT2\", \"HDAC6\", \"HMGB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}