Affinage

IPO8

Importin-8 · UniProt O15397

Round 2 corrected
Length
1037 aa
Mass
119.9 kDa
Annotated
2026-04-28
47 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IPO8 is a member of the importin-β superfamily that functions as a RanGTP-dependent nuclear import receptor, mediating nuclear translocation of diverse cargoes including SRP19, Argonaute proteins, and NF-κB/p65 (PMID:9214382, PMID:11682607, PMID:19167051, PMID:23906023). Beyond classical nuclear import, IPO8 is required for efficient cytoplasmic miRNA-guided gene silencing by recruiting Ago protein complexes to target mRNAs (PMID:19167051). IPO8 also participates in TGF-β/SMAD signaling homeostasis, as loss-of-function variants cause dysregulated nuclear pSmad2 accumulation and syndromic thoracic aortic aneurysm in both humans and knockout mice (PMID:34010605). Transcription of IPO8 is directly regulated by RUNX2 binding to the IPO8 promoter (PMID:27277970).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1997 High

    The discovery of IPO8 (RanBP8) as a RanGTP-binding member of the importin-β superfamily that competes with importin-β for nuclear pore binding sites established it as a candidate nuclear transport receptor.

    Evidence Biochemical binding assays and nuclear pore competition experiments with recombinant protein

    PMID:9214382

    Open questions at the time
    • No physiological cargo identified at this stage
    • Transport directionality in vivo not determined
  2. 2001 High

    Identification of SRP19 as the first cargo of IPO8 demonstrated that it functions as a bona fide nuclear import receptor for specific protein substrates.

    Evidence In vitro nuclear import reconstitution assay with SRP19 and immunofluorescence localization

    PMID:11682607

    Open questions at the time
    • Full cargo repertoire unknown
    • Structural basis of cargo recognition not determined
  3. 2009 High

    The finding that IPO8 interacts with Argonaute proteins and is required for Ago2 recruitment to target mRNAs expanded its role beyond nuclear import to cytoplasmic miRNA-mediated silencing.

    Evidence Co-immunoprecipitation, siRNA knockdown of IPO8 with Ago2–mRNA immunoprecipitation and microarray readout

    PMID:19167051

    Open questions at the time
    • Mechanism by which IPO8 facilitates Ago–mRNA engagement in the cytoplasm not resolved
    • Whether the cytoplasmic silencing role is independent of nuclear import activity remains unclear
  4. 2013 Medium

    Demonstrating that IPO8 imports NF-κB/p65 via an NLS-independent pathway revealed a non-canonical import mechanism and implicated IPO8 in inflammatory signaling.

    Evidence Systematic siRNA screen of importin-β family members with nuclear fractionation and NF-κB reporter assays after TNF-α stimulation

    PMID:23906023

    Open questions at the time
    • The p65 recognition surface on IPO8 has not been mapped
    • Relative contribution of IPO8 versus KPNB1 and XPO7 to p65 nuclear accumulation not quantified
  5. 2016 Medium

    Showing that RUNX2 directly binds the IPO8 promoter and drives its transcription linked upstream developmental regulation to nuclear import capacity during osteoblast differentiation.

    Evidence ChIP, luciferase reporter with deletion constructs, and RUNX2 siRNA knockdown

    PMID:27277970

    Open questions at the time
    • Other transcriptional regulators of IPO8 not surveyed
    • Functional consequence of reduced IPO8 on osteoblast cargo import not tested
  6. 2021 High

    Bi-allelic IPO8 loss-of-function variants causing syndromic thoracic aortic aneurysm in humans and mice established IPO8 as essential for TGF-β/SMAD signaling homeostasis and vascular integrity.

    Evidence Human genetic identification of bi-allelic LOF variants; Ipo8 knockout mouse with histology, pSmad2 IHC, RT-qPCR, and aortic compliance assays

    PMID:34010605

    Open questions at the time
    • Which SMAD isoform(s) are direct IPO8 import cargoes versus indirectly affected has not been resolved
    • Structural basis of IPO8-SMAD interaction unknown
  7. 2025 Medium

    Identification of a ternary IPO8–LINC1467–p65 complex that promotes NF-κB nuclear translocation during enterovirus infection revealed lncRNA-mediated regulation of IPO8 import activity in innate immunity.

    Evidence Co-immunoprecipitation of ternary complex, knockdown/overexpression assays, and mouse viral infection model

    PMID:41156681

    Open questions at the time
    • Whether LINC1467 binding modulates IPO8 conformation or cargo affinity is unknown
    • Generalizability of lncRNA-assisted IPO8 import to other cargoes or viral infections not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive structural model of IPO8 bound to its diverse cargoes is lacking, and how IPO8 discriminates between nuclear import substrates and participates in cytoplasmic mRNA silencing through a unified mechanism remains unresolved.
  • No high-resolution structure of IPO8 in complex with any cargo
  • Mechanism coupling nuclear import and cytoplasmic Ago-mRNA recruitment not clarified
  • Full catalogue of IPO8 cargoes not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 5 GO:0005635 nuclear envelope 1 GO:0005829 cytosol 1
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
AGO2RANRELARUNX2SRP19

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 IPO8 (RanBP8) was identified as a novel RanGTP-binding protein belonging to the importin-β superfamily. It binds RanGTP directly, prevents RanGAP1-mediated GTPase activation, and inhibits nucleotide exchange on RanGTP. It binds directly to nuclear pore complexes, competing for binding sites with importin-β and transportin, and undergoes Ran-dependent bidirectional transport across the nuclear envelope. Biochemical binding assays, nuclear pore competition assays, nuclear transport reconstitution The Journal of cell biology High 9214382
2001 IPO8 (importin 8) mediates nuclear import of SRP19 (the 19 kDa subunit of the signal recognition particle) in vitro, establishing SRP19 as the first identified cargo of importin 8. Endogenous SRP19 was shown to reside in the nucleus and nucleolus, consistent with nuclear SRP assembly. In vitro nuclear import assay, RNA microinjection, cDNA transfection, immunofluorescence localization of endogenous SRP19 Journal of cell science High 11682607
2009 IPO8 (Imp8) interacts with Argonaute (Ago) proteins and localizes to cytoplasmic P-bodies. Knockdown of Imp8 reduces nuclear Ago2 levels, indicating Imp8 facilitates nuclear localization of Ago2. Imp8 is required for efficient recruitment of Ago protein complexes to a large set of Ago2-associated target mRNAs, thereby enabling cytoplasmic miRNA-guided gene silencing. Co-immunoprecipitation, siRNA knockdown, fluorescence microscopy (P-body localization), Ago2-mRNA immunoprecipitation followed by microarray analysis Cell High 19167051
2013 IPO8, together with KPNB1 and XPO7, mediates nuclear translocation of NF-κB/p65. Knockdown of IPO8 reduced nuclear p65 after TNF-α stimulation and lowered NF-κB transcriptional activity. IPO8 imports p65 via an NLS-independent alternative pathway, as NLS-mutated p65 still bound to IPO8 and entered the nucleus. High-content siRNA screen of 17 importin-β family members, co-immunoprecipitation, nuclear fractionation, NF-κB reporter assay, TNF-α stimulation Traffic (Copenhagen, Denmark) Medium 23906023
2016 RUNX2 transcription factor binds directly to a specific sequence motif (positions −496 to −501 bp) in the IPO8 promoter and is required for maximal IPO8 basal transcription. ChIP confirmed RUNX2 occupancy at this site; RUNX2 knockdown reduced IPO8 mRNA levels, and IPO8 and RUNX2 expression were synchronized during osteoblast differentiation. ChIP-on-chip, dual luciferase reporter assay with truncation/deletion constructs, ChIP validation, siRNA knockdown of RUNX2 Molecular medicine reports Medium 27277970
2021 Bi-allelic loss-of-function variants in IPO8 cause syndromic thoracic aortic aneurysm (TAA). Ipo8 knockout mice recapitulate TAA with elastic fiber disorganization in aortic walls. Loss of IPO8 leads to nuclear accumulation of pSmad2, decreased Smad6/7 expression, and increased Mmp2 and Ccn2 (Ctgf), indicating dysregulated TGF-β signaling. Compliance assays showed augmented passive stiffness of the ascending aorta, linking IPO8-mediated nuclear import to TGF-β pathway homeostasis. Human genetics (bi-allelic LOF variants), C57BL/6N Ipo8 knockout mouse model, immunohistochemistry (pSmad2 nuclear localization), RT-qPCR, aortic compliance assays, histology American journal of human genetics High 34010605
2025 IPO8 forms a complex with the nuclear lncRNA LINC1467 and NF-κB/p65. LINC1467 interacts with IPO8 to facilitate phosphorylation and nuclear translocation of p65, promoting NF-κB-dependent pro-inflammatory cytokine expression as part of the antiviral innate immune response to enteroviruses. Co-immunoprecipitation (LINC1467/IPO8/p65 complex), knockdown/overexpression functional assays, reporter assays, mouse viral infection model Pathogens (Basel, Switzerland) Medium 41156681

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2015 Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 675 26168401
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1997 A novel class of RanGTP binding proteins. The Journal of cell biology 364 9214382
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2007 Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO reports 283 17932509
2009 Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell 281 19167051
2010 Human POGZ modulates dissociation of HP1alpha from mitotic chromosome arms through Aurora B activation. Nature cell biology 217 20562864
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2017 The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature communications 176 28685749
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2013 KPNB1, XPO7 and IPO8 mediate the translocation ofNF-κB/p65 into the nucleus. Traffic (Copenhagen, Denmark) 89 23906023
2001 Identification of a plasmid encoding SHV-12, TEM-1, and a variant of IMP-2 metallo-beta-lactamase, IMP-8, from a clinical isolate of Klebsiella pneumoniae. Antimicrobial agents and chemotherapy 81 11451699
2001 Signal recognition particle protein 19 is imported into the nucleus by importin 8 (RanBP8) and transportin. Journal of cell science 55 11682607
2008 Identification of importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens. BMC molecular biology 45 19014639
2011 First report of Klebsiella oxytoca strain coproducing KPC-2 and IMP-8 carbapenemases. Antimicrobial agents and chemotherapy 34 21422214
2012 Occurrence of IMP-8, IMP-10, and IMP-13 metallo-β-lactamases located on class 1 integrons and other extended-spectrum β-lactamases in bacterial isolates from Tunisian rivers. Scandinavian journal of infectious diseases 33 22992193
2015 Characterization of pKP-M1144, a Novel ColE1-Like Plasmid Encoding IMP-8, GES-5, and BEL-1 β-Lactamases, from a Klebsiella pneumoniae Sequence Type 252 Isolate. Antimicrobial agents and chemotherapy 31 26033721
2021 A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. American journal of human genetics 14 34010605
2019 Complete genome sequence of an IMP-8, CTX-M-14, CTX-M-3 and QnrS1 co-producing Enterobacter asburiae isolate from a patient with wound infection. Journal of global antimicrobial resistance 13 31181270
2014 Emergence of Citrobacter freundii carrying IMP-8 metallo-β-lactamase in Germany. New microbes and new infections 9 25356340
2010 First description of bla IMP-8 in a Pseudomonas mendocina isolated at the Hospital Infante D. Pedro, Aveiro, Portugal. Research in microbiology 9 20381610
2023 Analysis of NDM-1 and IMP-8 carbapenemase producing Raoultella planticola clinical isolates. Acta microbiologica et immunologica Hungarica 4 37478009
2024 Phenotypic and genotypic characterization of clinical carbapenem-resistant Acinetobacter species harboring the metallo-beta-lactamases IMP-8 or NDM-1 in China. Microbiology spectrum 3 39727411
2016 RUNX2 controls human IPO8 basal transcription in Saos-2 cells. Molecular medicine reports 3 27277970
2025 LINC1467 Activates the IPO8-p65 Axis to Restrict Hand, Foot, and Mouth Disease Virus Replication. Pathogens (Basel, Switzerland) 0 41156681
2023 Generation of one induced pluripotent cell (iPSC) line (BBANTWi011-A) from a patient carrying an IPO8 bi-allelic loss-of-function mutation. Stem cell research 0 36905820
2014 [Cloning of IPO8 promoter and analysis of its transcription activity]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 25202959