Affinage

IPO4

Importin-4 · UniProt Q8TEX9

Length
1081 aa
Mass
118.7 kDa
Annotated
2026-06-10
21 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IPO4 (Importin-4) is a karyopherin-family nuclear import receptor that delivers a structurally diverse set of cargoes into the nucleus to support chromatin assembly, DNA repair, and developmental gene programs (PMID:30177573, PMID:20805509). It binds newly synthesized histones H3.1 and H4 as monomers in the cytoplasm — independent of canonical histone chaperones — and releases them for incorporation into chromatin at replication sites (PMID:30177573). For several cargoes IPO4 engages an adaptor or bridging protein: C/EBPδ bridges FANCD2 to IPO4 to promote FANCD2 nuclear import and downstream monoubiquitination required for survival after DNA cross-linking damage (PMID:20805509), while IPO4 also drives nuclear translocation of CEBPD to activate PRKDC-mediated DNA repair (PMID:32661323) and imports the MMS22L–CDAN1 complex, a function disrupted in congenital dyserythropoietic anemia type 1 by a defective CDAN1–IPO4 interaction (PMID:41446536). IPO4 additionally facilitates nuclear accumulation of SOX2 (PMID:37923100). Cargo recognition uses an (L)PPRS(G/P)P NLS motif (PMID:36382187), and efficient transport requires docking on the FG-repeat region of the nucleoporin Nup98 (PMID:38780165). IPO4 abundance is set both transcriptionally, through competing ELK1 (repressor) and GABP (activator) Ets factors at its promoter (PMID:28254634), and post-translationally, through RNF180-mediated ubiquitination and degradation (PMID:37923100). Beyond receptor-mediated transport, the Drosophila ortholog APOLLO acts directly as a chromatin chaperone, depositing the protamine-like protein Mst77F while displacing histones during spermiogenesis (PMID:37660905).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Established that IPO4 is not merely a generic import receptor but functions through a defined adaptor, revealing how a DNA-repair factor is delivered to the nucleus to enable its activation.

    Evidence shRNA depletion, reciprocal co-IP of FANCD2-IPO4-C/EBPδ, nuclear import and monoubiquitination assays across MEFs, fibroblasts, and tumor cells

    PMID:20805509

    Open questions at the time
    • Structural basis of the C/EBPδ bridge to IPO4 not defined
    • Whether other DNA-repair cargoes use adaptor bridging unknown
  2. 2017 Medium

    Addressed how IPO4 levels are controlled, showing transcriptional tuning by opposing Ets-family factors at a core promoter.

    Evidence Promoter deletion, luciferase reporter, EMSA, and ELK1/GABP overexpression

    PMID:28254634

    Open questions at the time
    • Physiological signals that shift ELK1/GABP balance unknown
    • Tissue-specific relevance not addressed
  3. 2018 High

    Resolved how newly synthesized histones reach the nucleus, demonstrating IPO4 carries H3.1 and H4 as monomers independent of canonical histone chaperones.

    Evidence Tether-and-release import system, quantitative chaperone-binding co-IP, and live-cell imaging in human cells

    PMID:30177573

    Open questions at the time
    • Whether monomeric histone binding is structurally distinct from other cargo binding unknown
    • Handoff to chaperones after nuclear release not detailed
  4. 2020 Medium

    Extended IPO4's DNA-repair role to a second cargo, linking its import of CEBPD to transcriptional activation of a repair effector and chemoresistance.

    Evidence shRNA knockdown, nuclear fractionation/IF for CEBPD, PRKDC reporter assays, and cisplatin cytotoxicity in vitro and in xenografts

    PMID:32661323

    Open questions at the time
    • Direct NLS within CEBPD recognized by IPO4 not mapped
    • Single lab
  5. 2022 Low

    Began to define the cargo-recognition code, identifying a candidate NLS motif bound by IPO4.

    Evidence In silico motif discovery with in vitro binding validation in T47D cells

    PMID:36382187

    Open questions at the time
    • Partial experimental validation with limited mechanistic follow-up
    • Motif not validated across the diverse known cargoes
    • No structural confirmation of binding
  6. 2023 High

    Revealed a transport-independent activity, showing the Drosophila ortholog acts directly as a chromatin chaperone depositing a protamine-like protein during spermiogenesis.

    Evidence In vitro chromatin assembly/remodeling assays plus Drosophila Apollo loss-of-function with spermatid phenotypes

    PMID:37660905

    Open questions at the time
    • Whether mammalian IPO4 retains chaperone activity untested
    • Mechanism of histone displacement vs SNBP loading not resolved
  7. 2023 Medium

    Identified post-translational control of IPO4 and tied it to SOX2 nuclear delivery, placing IPO4 in a regulated degradation circuit.

    Evidence Co-IP, proteomics, ubiquitination assay, RNF180/IPO4 perturbation, nuclear fractionation for SOX2, and tumor assays

    PMID:37923100

    Open questions at the time
    • RNF180 ubiquitination site on IPO4 not mapped
    • Whether SOX2 import uses an adaptor unknown
  8. 2024 Medium

    Defined the nucleoporin docking requirement, showing IPO4 transport depends on FG-repeat binding to Nup98.

    Evidence Nucleoporin knockdowns, FG-to-SG mutagenesis, co-IP, and in vitro VDR transport assay

    PMID:38780165

    Open questions at the time
    • Whether other FG nucleoporins contribute not fully resolved
    • Stoichiometry of IPO4-Nup98 docking unknown
  9. 2024 Medium

    Placed IPO4 in an upstream regulatory axis, showing m6A-dependent mRNA stabilization by IMP2 raises IPO4 levels to drive CEBPD/PRKDC repair signaling and cisplatin resistance.

    Evidence RNA pull-down, RIP, co-IP, FISH, CRISPR screening, and in vitro/in vivo studies in bladder cancer

    PMID:39578867

    Open questions at the time
    • Direct demonstration of IPO4 mRNA m6A sites limited
    • Single lab
  10. 2025 Medium

    Connected IPO4 import to a Mendelian disease, identifying the MMS22L-CDAN1 complex as cargo whose defective import underlies congenital dyserythropoietic anemia type 1.

    Evidence Whole exome sequencing, complex analysis, MMS22L nuclear import assay, zebrafish haploinsufficiency, and human erythroid progenitor studies

    PMID:41446536

    Open questions at the time
    • Structural basis of the CDAN1-IPO4 contact not defined
    • How impaired MMS22L import disrupts erythropoiesis not fully resolved
  11. 2025 Medium

    Showed a viral protein hijacks IPO4 without being imported, revealing an interaction that relocalizes IPO4 and supports viral replication.

    Evidence Mass spectrometry, reciprocal co-IP, GST pull-down, Cap deletion mapping, and IPO4 knockdown viral replication assays

    PMID:41138500

    Open questions at the time
    • Mechanism by which Cap binding aids replication unclear
    • Whether Cap competes with cellular cargoes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the diverse IPO4 cargoes share a single structural recognition mode and whether mammalian IPO4 possesses the direct chromatin-chaperone activity seen in its Drosophila ortholog remain unresolved.
  • No structure of IPO4 bound to any cargo in the corpus
  • Conservation of APOLLO chaperone function in mammals untested
  • Unified NLS code across histones, FANCD2, CEBPD, SOX2, and MMS22L-CDAN1 not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 5
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-4839726 Chromatin organization 2 R-HSA-73894 DNA Repair 2
Partners
CDAN1CEBPDFANCD2MMS22LNUP98RNF180SOX2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Human histones H3.1 and H4 are imported into the nucleus as monomers bound to IPO4 (importin-alpha proteins, predominantly IPO4), not as H3-H4 dimers complexed with histone chaperones. Cytosolically tethered H3.1 and H4 were found associated with IPO4 but not with NASP, ASF1a, RbAp46, or HAT1. Release of monomeric histones resulted in rapid nuclear translocation, IPO4 dissociation, and incorporation into chromatin at replication sites. Tether-and-release system for studying import dynamics of newly synthesised histones; co-immunoprecipitation; quantitative analysis of histone-chaperone associations; live-cell imaging The EMBO journal High 30177573
2010 IPO4 mediates nuclear import of FANCD2, a prerequisite for FANCD2 monoubiquitination and its function in replication-associated DNA repair. C/EBPδ bridges the interaction between FANCD2 and IPO4 via separate domains, augmenting FANCD2-IPO4 association and nuclear translocation. Loss of C/EBPδ or IPO4 impairs FANCD2 monoubiquitination and reduces survival after DNA cross-linking damage. Gene knockout, protein depletion (shRNA), overexpression; co-immunoprecipitation to detect FANCD2-IPO4-C/EBPδ complex; nuclear import assay; monoubiquitination assay in MEFs, human fibroblasts, and breast tumor cells Proceedings of the National Academy of Sciences of the United States of America High 20805509
2020 IPO4 augments nuclear translocation of CEBPD via its nuclear localization signals (NLS), enabling CEBPD to transcriptionally upregulate PRKDC (DNA-PKcs), which mediates DNA damage repair in response to cisplatin. Knockdown of IPO4 reduced CEBPD nuclear accumulation, decreased PRKDC expression, and enhanced cisplatin-induced cytotoxicity in vitro and in vivo. shRNA knockdown of IPO4 and CEBPD; nuclear fractionation/immunofluorescence for CEBPD localization; reporter assays for PRKDC transcription; in vitro and in vivo (xenograft) cytotoxicity assays Oncogene Medium 32661323
2023 In Drosophila, APOLLO (a testis-specific ortholog of IPO4) mediates the deposition of protamine-like protein Mst77F onto DNA and oligonucleosome templates while displacing histones, functioning as a dual histone- and SNBP-specific chromatin chaperone. In vivo, loss-of-function mutation of Apollo causes defective Mst77F loading, abnormal sperm morphology, and male infertility. In vitro biochemical assays (chromatin assembly/remodeling); Drosophila genetics (Apollo mutant); immunofluorescence for Mst77F loading in spermatid nuclei The Journal of biological chemistry High 37660905
2023 RNF180, an E3 ubiquitin ligase, interacts with IPO4 and promotes its ubiquitination and degradation. IPO4 in turn binds SOX2 and facilitates SOX2 nuclear translocation; IPO4 knockdown decreases nuclear SOX2 and increases p21 expression. RNF180 overexpression inhibits nuclear SOX2 accumulation through IPO4 ubiquitin-mediated degradation. Co-immunoprecipitation; proteomics; overexpression/knockdown of RNF180 and IPO4; nuclear fractionation for SOX2; ubiquitination assay; in vitro and in vivo tumor assays Cellular signalling Medium 37923100
2022 The sequence motif (L)PPRS(G/P)P was identified as a nuclear localization signal (NLS) recognized by Importin 4 (IPO4) for binding cargo proteins. This motif was validated experimentally in the breast cancer cell line T47D using in vitro binding assays. In silico unsupervised motif discovery followed by in vitro experimental validation (binding assays) in T47D cells; EMSA-like validation Computational and structural biotechnology journal Low 36382187
2024 Nucleoporin Nup98 is required for efficient IPO4-mediated nuclear import. Depletion of Nup98 shifts IPO4 subcellular localization from cytoplasm to nucleus. Nup98 physically interacts with IPO4 through its N-terminal FG-repeat region; mutation of FG to SG motifs (particularly residues 121-360) significantly attenuates Nup98-IPO4 binding. In vitro transport assay showed that IPO4 substrate VDR cannot be transported into the nucleus after Nup98 knockdown. shRNA knockdown of nucleoporins (Nup358, Nup153, Nup98, Nup50); subcellular localization assay; mutational analysis of FG repeats; co-immunoprecipitation; in vitro transport assay with VDR Journal of cellular biochemistry Medium 38780165
2024 IMP2 enhances mRNA stability of IPO4 in an m6A-dependent manner, leading to increased IPO4 protein levels that augment nuclear translocation of C/EBPδ and thereby activate PRKDC-mediated DNA damage repair in cisplatin-resistant bladder cancer. IMP2 inhibition reduces IPO4 levels and sensitizes cells to cisplatin. RNA pull-down; co-immunoprecipitation; RNA immunoprecipitation; immunofluorescence; FISH; CRISPR screening; in vitro and in vivo functional studies Cancer cell international Medium 39578867
2025 IPO4 directly interacts with the N-terminal residues 1-100 of porcine circovirus type 2 (PCV2) capsid protein (Cap). This interaction does not trigger nuclear import of Cap or affect Cap degradation, but causes IPO4 to translocate from the cytoplasm to the nucleus. IPO4 knockdown significantly reduced intracellular Cap levels and inhibited PCV2 replication. Mass spectrometry; co-immunoprecipitation; GST pull-down; deletion mapping of Cap; subcellular localization assay; shRNA knockdown of IPO4; viral replication assay Veterinary microbiology Medium 41138500
2025 MMS22L and CDAN1 are components of the same protein complex whose nuclear import is mediated by IPO4. In congenital dyserythropoietic anemia type 1 (CDA1) patients, a defective interaction between CDAN1 and IPO4 impairs nuclear import of MMS22L, linking IPO4-mediated import to erythropoiesis regulation. Whole exome sequencing; protein complex analysis; nuclear import assay for MMS22L; zebrafish haploinsufficiency model; human erythroid progenitor loss-of-function studies HemaSphere Medium 41446536
2017 IPO4 transcription is competitively regulated by two Ets-family transcription factors: ELK1 represses IPO4 promoter activity while GABP activates it. A core promoter region (nt -118 to +108) containing two Ets binding sites is required for promoter activity. ELK1 and GABP compete for these sites, and their overexpression results in down-regulation or up-regulation of IPO4 expression, respectively. Promoter deletion analysis; luciferase reporter assay; EMSA; overexpression of ELK1 and GABP Gene Medium 28254634

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Fas-mediated apoptosis in human prostatic carcinoma cell lines. Cancer research 198 9135020
2018 Evidence for the nuclear import of histones H3.1 and H4 as monomers. The EMBO journal 44 30177573
2010 CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 35 20805509
2020 Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer. Oncogene 30 32661323
1992 Monoclonal antibodies of IPO series against B cell differentiation antigens in leukemia and lymphoma immunophenotyping. Neoplasma 26 1528302
2019 POLR1B is upregulated and promotes cell proliferation in non-small cell lung cancer. Oncology letters 19 31897183
2024 IMP2 drives chemoresistance by repressing cisplatin-induced apoptosis and ferroptosis via activation of IPO4 and SLC7A11 under hypoxia in bladder cancer. Cancer cell international 11 39578867
2019 Importin-4 functions as a driving force in human primary gastric cancer. Journal of cellular biochemistry 11 30861176
2023 E3 ubiquitin ligase RNF180 impairs IPO4/SOX2 complex stability and inhibits SOX2-mediated malignancy in ovarian cancer. Cellular signalling 7 37923100
2023 APOLLO, a testis-specific Drosophila ortholog of importin-4, mediates the loading of protamine-like protein Mst77F into sperm chromatin. The Journal of biological chemistry 6 37660905
2017 Competitive regulation of IPO4 transcription by ELK1 and GABP. Gene 6 28254634
1990 [Monoclonal antibodies of the IPO series in studying and diagnosing malignant lymphoproliferative diseases]. Gematologiia i transfuziologiia 5 2373343
2023 Integrative analysis of the proteome and transcriptome in gastric cancer identified LRP1B as a potential biomarker. Biomarkers in medicine 4 36606427
2023 Data-independent acquisition (DIA) mass spectrometry reveals related proteins involved in the occurrence of early intestinal-type gastric cancer. Medical oncology (Northwood, London, England) 4 38114688
2023 Research on the resistance of isoviolanthin to hydrogen peroxide-triggered injury of skin keratinocytes based on Transcriptome sequencing and molecular docking. Medicine 3 38013320
2022 Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation. Computational and structural biotechnology journal 3 36382187
2025 MMS22L is a novel key actor of normal and pathological erythropoiesis. HemaSphere 1 41446536
2024 Nucleoporin Nup98 is an essential factor for ipo4 dependent protein import. Journal of cellular biochemistry 1 38780165
2024 Identification of the whole genome of alternative splicing and RNA-binding proteins involved in nintedanib-induced apoptosis in gastric cancer cells. PeerJ 1 39726754
2025 Nuclear transport factor IPO4 modifies localization by PCV2 and facilitates viral replication. Veterinary microbiology 0 41138500
1990 [Monoclonal antibodies IPO-4 recognizing antigen-activated human T and B lymphocytes]. Eksperimental'naia onkologiia 0 2344819

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