Affinage

XPO5

Exportin-5 · UniProt Q9HAV4

Length
1204 aa
Mass
136.3 kDa
Annotated
2026-06-11
34 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

XPO5 (exportin-5) is a nuclear export receptor central to microRNA biogenesis, acting at multiple steps from nuclear pri-miRNA processing to cytoplasmic delivery of pre-miRNAs (PMID:32296071). It pervasively binds double-stranded regions of clustered primary miRNA precursors and structured RNAs such as vault RNAs in a RanGTP-independent manner and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs; genetic deletion compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis (PMID:32296071). Beyond pre-miRNA cargo, XPO5 directly binds and exports Dicer mRNA, so that competing structured RNAs that titrate XPO5 away from Dicer mRNA reduce Dicer protein levels (PMID:21297638). XPO5 export activity is governed by a phosphorylation switch: ERK phosphorylation at a Ser-Pro motif licenses Pin1 WW-domain binding and a Pin1-catalyzed conformational change that retains XPO5 in the nucleus and diminishes pre-miRNA export, promoting hepatocellular carcinoma (PMID:29445125), while the PP2A-B55β holoenzyme dephosphorylates XPO5 to restore its cytoplasmic distribution, pre-miRNA export and mature miRNA levels, opposing HCC (PMID:35441157). This switch is tuned by additional partners: METTL1 facilitates ERK-mediated phosphorylation to drive nuclear retention independently of its m7G methyltransferase activity (PMID:41591839), and the lipid kinase PIP5K1A binds XPO5 in the nucleus and blocks pre-let-7 binding in a kinase-independent manner (PMID:37655623). XPO5 also interacts with NUP93 and SMAD4 at the nuclear pore, and NUP93 mutations causing steroid-resistant nephrotic syndrome disrupt the NUP93-SMAD4 interaction and BMP7-induced SMAD signaling in podocytes (PMID:26878725).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Established that XPO5 cargo extends beyond pre-miRNAs to a protein-coding mRNA, linking XPO5 directly to Dicer abundance and explaining how competing structured RNAs can suppress the miRNA pathway.

    Evidence In vitro binding, cellular RNA-IP, and competition by pre-miRNA/VA1 RNA in XPO5-knockdown cells

    PMID:21297638

    Open questions at the time
    • Does not define the cis-elements in Dicer mRNA recognized by XPO5
    • Does not establish whether other mRNAs are XPO5 cargo
  2. 2016 Medium

    Placed XPO5 in a nuclear-pore complex with NUP93 and SMAD4, connecting the export receptor to BMP7/SMAD signaling and a Mendelian kidney disease.

    Evidence Co-IP of XPO5-NUP93, SMAD transcriptional reporter, patient NUP93 mutation analysis in podocytes

    PMID:26878725

    Open questions at the time
    • XPO5's own functional contribution within the NUP93-SMAD4 complex is not isolated
    • No XPO5 mutation directly tested for the nephrotic phenotype here
  3. 2018 High

    Defined the regulatory logic that switches XPO5 off, showing ERK phosphorylation plus Pin1 isomerization conformationally suppresses pre-miRNA export to drive tumorigenesis.

    Evidence Domain-mapped Co-IP of Pin1 WW with phospho-XPO5, Pin1 shRNA, export assays, HCC models in vitro and in vivo

    PMID:29445125

    Open questions at the time
    • Structural basis of the Pin1-induced conformational change not resolved
    • Identity of the upstream stimulus activating ERK toward XPO5 not defined
  4. 2020 High

    Reframed XPO5 as a nuclear enhancer of microprocessor activity, not merely an exporter, by showing RanGTP-independent binding to clustered pri-miRNAs and vault RNAs and an essential developmental role.

    Evidence CLIP-seq RNA profiling, DROSHA/DGCR8 processing assays, and XPO5-KO mouse phenotyping

    PMID:32296071

    Open questions at the time
    • Mechanism by which XPO5 stimulates DROSHA/DGCR8 processing not defined at atomic level
    • Relative contribution of nuclear processing vs export to the KO phenotype not separated
  5. 2022 Medium

    Identified the phosphatase arm of the XPO5 switch, showing PP2A-B55β reverses ERK phosphorylation to restore export and suppress HCC.

    Evidence Phosphatase identification, Co-IP of PP2A B55β with XPO5, fractionation, HCC models

    PMID:35441157

    Open questions at the time
    • Single-lab characterization
    • Site specificity of dephosphorylation not mapped
  6. 2023 Medium

    Revealed a kinase-independent inhibitory partner, with nuclear PIP5K1A blocking XPO5's pre-let-7 binding and tying the interaction to the conserved lin-28/let-7 heterochronic pathway.

    Evidence Co-IP, pre-miRNA binding competition, kinase-dead mutant analysis, C. elegans lin-28/let-7 epistasis

    PMID:37655623

    Open questions at the time
    • Structural basis for competition with pre-miRNA not resolved
    • Generality across pre-miRNAs beyond let-7 not established
  7. 2024 Medium

    Showed XPO5 is a target of viral pathway suppression, as SARS-CoV-2 N protein drives its autophagic degradation to inhibit miRNA biogenesis and worsen lung pathology.

    Evidence XPO5 knockdown/overexpression in lung cells and mice, autophagic degradation assay, in vivo pneumonia severity

    PMID:39138195

    Open questions at the time
    • Autophagy receptor/adaptor targeting XPO5 not identified
    • Selectivity of N-protein for XPO5 vs co-degraded factors not dissected
  8. 2025 Medium

    Showed METTL1 controls the XPO5 phosphorylation switch independently of its methyltransferase activity by facilitating ERK-mediated phosphorylation and nuclear retention.

    Evidence APEX2 proximity labeling/LC-MS/MS, Co-IP, METTL1-KO fractionation, constitutively active ERK rescue

    PMID:41591839

    Open questions at the time
    • How METTL1 promotes ERK activity toward XPO5 mechanistically unresolved
    • Single-study, single-lab finding
  9. 2025 Low

    Extended XPO5 cargo to m6A-modified lncRNA export via a YTHDC1/SRSF3/ALYREF complex, though XPO5's individual contribution is not isolated.

    Evidence Co-IP/complex assembly, phase separation assays, m6A and nuclear export assays with component knockdowns

    PMID:40221424

    Open questions at the time
    • XPO5's specific mechanistic role in the complex not individually resolved
    • Inferred complex membership from Co-IP in a single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XPO5's distinct activities — RanGTP-independent pri-miRNA processing enhancement versus RanGTP-coupled export of pre-miRNAs and mRNAs — are coordinated on a single receptor, and what structural states the phosphorylation/conformational switch toggles between, remain unresolved.
  • No structural model of phospho- vs dephospho-XPO5 cargo states
  • Cargo selection rules across pre-miRNA, mRNA, and lncRNA not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0140104 molecular carrier activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9609507 Protein localization 2
Partners
METTL1NUP93PIN1PIP5K1APP2A-B55ΒSMAD4YTHDC1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 XPO5 (exportin-5) directly binds Dicer mRNA and mediates its nuclear export; inhibition of XPO5 causes increased nuclear retention of Dicer mRNA and reduced Dicer protein levels. Overexpression of pre-miRNA or adenoviral VA1 RNA titrates XPO5 away from Dicer mRNA, reducing Dicer levels and enhancing viral replication. In vitro binding assays, cellular RNA immunoprecipitation, XPO5 inhibition/knockdown, overexpression of competing RNAs Nature structural & molecular biology High 21297638
2018 ERK-induced phosphorylation of XPO5 at a Serine-Proline (pS-P) motif enables binding by Pin1's WW domain; Pin1 then catalyzes a conformational change in XPO5 that diminishes its ability to export pre-miRNAs from the nucleus, resulting in reduced mature miRNA levels and promoted hepatocellular carcinoma development. Co-IP (Pin1 WW domain binding to phospho-XPO5), shRNA knockdown of Pin1, in vitro and in vivo HCC models, pre-miRNA nuclear export assays Cell death and differentiation High 29445125
2020 XPO5 pervasively binds double-stranded RNA regions in clustered primary miRNA precursors (pri-miRNAs such as mir-17~92 and mir-15b~16-2) and vault RNAs in a RanGTP-independent manner, and enhances DROSHA/DGCR8 microprocessor processing of these pri-miRNAs. Genetic deletion of XPO5 compromises biogenesis of most miRNAs and causes severe defects in mouse embryonic development and skin morphogenesis. Global XPO5-associated RNA profiling (CLIP-seq), genetic deletion (KO mice), pri-miRNA processing assays with DROSHA/DGCR8, RanGTP-independence demonstrated biochemically Nature communications High 32296071
2022 The phosphatase PP2A, specifically the B55β regulatory subunit-containing holoenzyme, dephosphorylates XPO5, reversing ERK-mediated phosphorylation; dephosphorylation favors XPO5 cytoplasmic distribution, promotes pre-miRNA export, and increases mature miRNA expression, leading to HCC inhibition in vitro and in vivo. Phosphatase identification assay, co-IP of PP2A subunits with XPO5, subcellular fractionation, in vitro and in vivo HCC models MedComm Medium 35441157
2016 XPO5 (exportin 5) interacts with NUP93 and SMAD4; mutations in NUP93 that cause steroid-resistant nephrotic syndrome abrogate the NUP93–SMAD4 interaction and interfere with BMP7-induced SMAD transcriptional reporter activity, placing XPO5 in a complex with NUP93 at the nuclear pore relevant to SMAD signaling in podocytes. Co-IP (XPO5–NUP93 interaction), SMAD transcriptional reporter assay, patient mutation analysis, NUP93 knockdown Nature genetics Medium 26878725
2023 Lipid kinase PIP5K1A interacts with XPO5 in the nucleus and blocks XPO5 binding to pre-let-7 miRNA, thereby reducing mature let-7 levels; this function of PIP5K1A is kinase-independent. In C. elegans, the ortholog PPK-1 functions in the lin-28/let-7 heterochronic pathway controlling seam cell developmental timing. Co-IP (PIP5K1A–XPO5 interaction in nucleus), pre-miRNA binding competition assay, C. elegans genetic pathway (lin-28/let-7 epistasis), kinase-dead mutant analysis Nucleic acids research Medium 37655623
2025 METTL1 interacts with XPO5 in the nucleus (validated by co-IP); genetic ablation of METTL1 redistributes XPO5 to the cytosol, accelerating pre-miRNA export and enhancing miRNA maturation. Mechanistically, METTL1 facilitates ERK-mediated phosphorylation of XPO5, promoting its nuclear retention; constitutive ERK activation restores nuclear XPO5 in METTL1-deficient cells. This function is independent of METTL1's canonical m7G methyltransferase activity. APEX2 proximity labeling coupled with LC-MS/MS (interactome), co-IP and western blot, METTL1 KO cells, subcellular fractionation, constitutively active ERK rescue experiment Nucleic acids research Medium 41591839
2024 SARS-CoV-2 N protein induces autophagic degradation of XPO5 (along with Dicer, SRSF3, and hnRNPA3), thereby inhibiting miRNA biogenesis; XPO5 knockdown exacerbates N protein-induced pneumonia severity, while XPO5 overexpression decreases it. XPO5 knockdown and overexpression in lung cells/mice, autophagic degradation assay, N protein expression, in vivo pneumonia severity assessment Nature communications Medium 39138195
2025 YTHDC1 phase separation promotes nuclear export of m6A-modified lncRNA by forming a nuclear pore complex with SRSF3, ALYREF, and XPO5, facilitating translocation from nucleus to cytoplasm; XPO5 participates as a component of this export complex. Co-IP/complex assembly, phase separation assays, m6A modification analysis, nuclear export assays, knockdown of complex components Cell death & disease Low 40221424
2025 Melatonin inhibits ERK-mediated phosphorylation of XPO5, which promotes nuclear transport of pre-miR-590-5p (shown to bind XPO5 by RNA immunoprecipitation) and enhances chondrogenic differentiation of human bone marrow mesenchymal stem cells. RNA immunoprecipitation (XPO5–pre-miR-590-5p interaction), western blot for ERK/XPO5 phosphorylation, chondrogenic differentiation assay with MLT treatment Molecular biology reports Low 40549108

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nature genetics 160 26878725
2011 Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. Nature structural & molecular biology 81 21297638
2010 Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis. International journal of molecular epidemiology and genetics 53 21552306
2018 Pin1 impairs microRNA biogenesis by mediating conformation change of XPO5 in hepatocellular carcinoma. Cell death and differentiation 44 29445125
2020 XPO5 promotes primary miRNA processing independently of RanGTP. Nature communications 37 32296071
2013 Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women. Menopause (New York, N.Y.) 27 23549446
2013 A miR-SNP of the XPO5 gene is associated with advanced non-small-cell lung cancer. OncoTargets and therapy 26 23874110
2017 Association of microRNA-related gene XPO5 rs11077 polymorphism with susceptibility to thyroid cancer. Medicine 23 28383405
2013 A microRNA-related single nucleotide polymorphism of the XPO5 gene is associated with survival of small cell lung cancer patients. Biomedical reports 20 24648983
2017 Perinatal protein malnutrition alters expression of miRNA biogenesis genes Xpo5 and Ago2 in mice brain. Neuroscience letters 18 28300636
2025 YTHDC1 phase separation drives the nuclear export of m6A-modified lncNONMMUT062668.2 through the transport complex SRSF3-ALYREF-XPO5 to aggravate pulmonary fibrosis. Cell death & disease 15 40221424
2016 Downregulation and tumor-suppressive role of XPO5 in hepatocellular carcinoma. Molecular and cellular biochemistry 14 27000860
2022 Regulation of XPO5 phosphorylation by PP2A in hepatocellular carcinoma. MedComm 11 35441157
2020 Association of microRNA biosynthesis genes XPO5 and RAN polymorphisms with cancer susceptibility: Bayesian hierarchical meta-analysis. Journal of Cancer 11 32127945
2023 Unleash Multifunctional Role of miRNA Biogenesis Gene Variants (XPO5*rs34324334 and RAN*rs14035) with Susceptibility to Hepatocellular Carcinoma. Journal of personalized medicine 9 37373948
2019 Genetic variants in DICER1, DROSHA, RAN, and XPO5 genes and risk of pregnancy-induced hypertension. Pregnancy hypertension 9 31056154
2019 Influence of genetic polymorphisms in DICER and XPO5 genes on the risk of coronary artery disease and circulating levels of vascular miRNAs. Thrombosis research 8 31185329
2024 SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia. Nature communications 7 39138195
2018 Evaluating the Oncogenic and Tumor Suppressor Role of XPO5 in Different Tissue Tumor Types. Asian Pacific journal of cancer prevention : APJCP 7 29699373
2020 Single-Nucleotide Polymorphisms in XPO5 are Associated with Noise-Induced Hearing Loss in a Chinese Population. Biochemistry research international 5 32148964
2020 Analysis of microRNA processing machinery gene (DROSHA, DICER1, RAN, and XPO5) variants association with end-stage renal disease. Journal of clinical laboratory analysis 5 32770606
2023 Altered MicroRNA Maturation in Ischemic Hearts: Implication of Hypoxia on XPO5 and DICER1 Dysregulation and RedoximiR State. Antioxidants (Basel, Switzerland) 3 37507877
2023 Lipid kinase PIP5K1A regulates let-7 microRNA biogenesis through interacting with nuclear export protein XPO5. Nucleic acids research 3 37655623
2021 Effects of Knockdown of XPO5 by siRNA on the Biological Behavior of Head and Neck Cancer Cells. The Laryngoscope 3 34328643
2019 Association between XPO5 rs11077 polymorphism and cancer susceptibility: a meta-analysis of 7284 cases and 8511 controls. Experimental oncology 2 31868332
2018 Frequency distribution of BLMH, XPO5 and HFE gene polymorphisms in the South Indian population and their association with Hodgkin Lymphoma. The International journal of biological markers 2 29683071
2026 METTL1 interacts with XPO5 to modulate pre-miRNA export. Nucleic acids research 1 41591839
2025 Tumor-derived exosomal lncRNA SNHG4 promotes triple-negative breast cancer progression by targeting XPO5. Frontiers in oncology 1 40657248
2023 Investigation of the association of the RAN (rs14035) and XPO5 (rs11077) polymorphisms with venous thromboembolism. Romanian journal of internal medicine = Revue roumaine de medecine interne 1 37311119
2022 Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis. Human genomics 1 36371311
2016 [The analysis of single nucleotide polymorphisms of the DGCR8 and XPO5 genes, and their association with the incidence of primary open angle glaucoma]. Klinika oczna 1 29912490
2025 Melatonin-mediated Inhibition of XPO5 phosphorylation facilitates the chondrogenic differentiation of human bone marrow mesenchymal stem cells by regulating the transport of miR-590-5p. Molecular biology reports 0 40549108
2025 XPO5 Polymorphism in Colon Cancer Patients: A Cross-Sectional Study. International journal of molecular sciences 0 41516223
2024 Relationship Between the Occurrence of Depression and DROSHA (rs6877842, rs10719) and XPO5 (rs11077) Single-Nucleotide Polymorphisms in the Polish Population: A Case-Control Study. International journal of molecular sciences 0 39596271

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