Affinage

GEMIN4

Gem-associated protein 4 · UniProt P57678

Length
1058 aa
Mass
120.0 kDa
Annotated
2026-06-10
18 papers in source corpus 8 papers cited in narrative 13 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

GEMIN4 is an essential component of the SMN complex that functions in spliceosomal snRNP assembly and pre-mRNA splicing (PMID:10725331). It binds directly to the DEAD-box protein Gemin3, acting as its cofactor, and contacts several Sm core proteins of spliceosomal snRNPs, and the SMN/Gemin4 complex immunoprecipitates assembling U snRNAs such as U1 and U5 (PMID:10725331). GEMIN4 also engages galectin-1 and galectin-3, which associate with the SMN complex, and the galectin-3 N-terminal domain arrests pre-mRNA at the H-complex in cell-free splicing assays, linking the GEMIN4/galectin interaction to spliceosome assembly (PMID:11522829). The protein shuttles between cytoplasm, nuclear gems, and nucleoli, and a canonical N-terminal NLS is necessary and sufficient for its nuclear import; overexpression drives SMN and partner Gemin proteins into the nucleus and disrupts Cajal body organization, while NLS-deficient GEMIN4 sequesters Gemin2 and Gemin3 in the cytoplasm (PMID:10725331, PMID:18675250, PMID:29371219). Gemin4-null mice die early in embryogenesis, establishing it as an essential mammalian gene consistent with its role in snRNP biogenesis (PMID:29371219). Beyond its core splicing function, GEMIN4 acts as a transcriptional corepressor of the mineralocorticoid receptor through an MPxLxxLL motif (PMID:25555524), and its cytoplasmic sequestration by the micropeptide XLH-36 impairs S100A4 mRNA splicing to promote epithelial-mesenchymal transition and triple-negative breast cancer metastasis (PMID:41315668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 High

    Establishing that Gemin4 is a stable subunit of the SMN complex and a direct Gemin3 partner defined its molecular home and its likely role as a Gemin3 cofactor in snRNP assembly.

    Evidence Nanoelectrospray mass spectrometry, co-IP, and direct interaction assays; immunoprecipitation of U1/U5 snRNAs from Xenopus oocyte cytoplasm; immunolocalization to cytoplasm, gems, and nucleoli

    PMID:10725331

    Open questions at the time
    • Stoichiometry and architecture of Gemin4 within the SMN complex not resolved
    • Functional consequence of the Sm-protein contacts not mechanistically dissected
    • Nucleolar role inferred from localization, not from a functional assay
  2. 2001 High

    Identifying galectin-1 and galectin-3 as direct GEMIN4 partners that join the SMN complex connected GEMIN4 to spliceosome assembly through a galectin-dependent step.

    Evidence Yeast two-hybrid, GST pull-down, co-IP from HeLa nuclear extracts, and a cell-free splicing assay with a dominant-negative galectin-3 N-terminal fragment

    PMID:11522829

    Open questions at the time
    • Endogenous requirement for galectins in GEMIN4-dependent splicing not tested by loss-of-function
    • Whether the galectin interaction occurs constitutively or under specific conditions unknown
  3. 2003 Medium

    A GEMIN4 variant (HCAP1) was shown to bind zinc-finger proteins including NDP52 via a leucine-zipper interface, hinting at cytoplasmic interactions beyond the core SMN complex.

    Evidence Yeast two-hybrid, GST pull-down, co-IP, immunofluorescence, and deletion mapping

    PMID:12869526

    Open questions at the time
    • Functional significance of the NDP52 interaction not established
    • Relationship of this interaction to snRNP assembly unknown
  4. 2004 Medium

    Overexpression of GEMIN4 haplotypes suppressed hepatocellular carcinoma cell growth, providing an early link between GEMIN4 and proliferation control.

    Evidence Transfection, colony formation and growth assays, and Atlas gene expression profiling in Hep3B cells

    PMID:14603441

    Open questions at the time
    • Mechanism connecting GEMIN4 to growth suppression not defined
    • Phenotype based on overexpression, not endogenous loss of function
  5. 2008 Medium

    Mapping a canonical N-terminal NLS that is necessary and sufficient for nuclear import explained how GEMIN4 traffics to the nucleus.

    Evidence Deletion/truncation constructs and subcellular localization assays

    PMID:18675250

    Open questions at the time
    • Import receptor mediating NLS recognition not identified
    • Regulation of shuttling between compartments not addressed
  6. 2015 Medium

    Discovery that GEMIN4 represses mineralocorticoid receptor transactivation via an MPxLxxLL motif extended its function to transcriptional coregulation.

    Evidence Reporter assays in HEK293 and H9c2 cells, siRNA knockdown, endogenous target gene measurement, and co-localization with MR

    PMID:25555524

    Open questions at the time
    • Whether MR corepression is independent of the SMN/splicing role unknown
    • Tissue specificity and physiological relevance not established in vivo
  7. 2018 High

    Genetic ablation and overexpression experiments confirmed GEMIN4 as essential for mammalian development and showed it can drive SMN complex nuclear import, while refining which NLS controls which cargo.

    Evidence Gemin4-null mouse knockout, crosses with SMA model mice, and dose-dependent overexpression with NLS deletion analysis tracking SMN, Gemin2/3, and coilin

    PMID:29371219

    Open questions at the time
    • Heterozygous loss did not modify SMA phenotype, leaving its relationship to SMA unresolved
    • Developmental stage and tissue requirements of essentiality not detailed
    • Mechanism by which NLS-deleted Gemin4 selectively retains Gemin2/3 but not SMN unclear
  8. 2025 Medium

    Identifying the micropeptide XLH-36 as a cytoplasmic sequestrant of GEMIN4 linked GEMIN4-dependent splicing of S100A4 to cancer metastasis.

    Evidence Binding/co-IP assays, XLH-36 knockout xenograft model, mRNA splicing assay, and ICAM1/EMT readouts

    PMID:41315668

    Open questions at the time
    • Direct demonstration that GEMIN4 catalyzes/promotes S100A4 splicing in a defined system not shown
    • Generality of GEMIN4 as a metastasis regulator beyond TNBC unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GEMIN4's distinct activities — snRNP assembly cofactor, nuclear import driver, transcriptional corepressor, and metastasis-linked splicing regulator — are coordinated within one protein remains unresolved.
  • No structural model of GEMIN4 within the SMN complex
  • No reconstitution defining GEMIN4's direct biochemical contribution to splicing
  • Whether non-splicing roles (MR corepression, S100A4 regulation) are separable from the core SMN function is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0003723 RNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
GEMIN2GEMIN3LGALS1LGALS3NDP52NR3C2SMN1XLH-36
Complex memberships
SMN complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Gemin4 is a component of the SMN complex, identified by nanoelectrospray mass spectrometry, and interacts directly with Gemin3 (a DEAD box protein), suggesting it acts as a cofactor for Gemin3. Nanoelectrospray mass spectrometry, co-immunoprecipitation, direct interaction assays The Journal of cell biology High 10725331
2000 Gemin4 interacts directly with several Sm core proteins of spliceosomal snRNPs. Direct interaction assays, co-immunoprecipitation The Journal of cell biology Medium 10725331
2000 Monoclonal antibodies against Gemin4 efficiently immunoprecipitate spliceosomal U snRNAs U1 and U5 from Xenopus oocytes cytoplasm, placing the SMN/Gemin4 complex in snRNP assembly. Immunoprecipitation from Xenopus oocyte cytoplasm The Journal of cell biology Medium 10725331
2000 Gemin4 co-localizes with SMN in the cytoplasm and in nuclear gems, and is also detected in nucleoli, suggesting a potential role in pre-ribosomal RNA processing or ribosome assembly. Immunolocalization (immunofluorescence microscopy) The Journal of cell biology Medium 10725331
2001 Gemin4 directly interacts with galectin-1 (identified by yeast two-hybrid and confirmed by GST pull-down), and galectin-3 also interacts with Gemin4; both galectins associate with the SMN complex containing SMN, Gemin2, and Sm polypeptides. Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation from HeLa nuclear extracts Nucleic acids research High 11522829
2001 Galectin-3 N-terminal domain (but not intact galectin-3 or its C-terminal domain) added to a cell-free splicing assay inhibits splicing in a dose-dependent manner and arrests pre-mRNA at the H-complex, implicating the Gemin4/galectin interaction in spliceosome assembly. Cell-free pre-mRNA splicing assay, native gel electrophoresis Nucleic acids research Medium 11522829
2003 HCAP1 (a variant of GEMIN4) interacts with five zinc-finger proteins identified by yeast two-hybrid; the strongest interaction is with NDP52, confirmed by GST pull-down and co-immunoprecipitation. The leucine zipper domain of HCAP1 and the zinc-finger domain of NDP52 mediate the interaction. NDP52 co-localizes with HCAP1 in the cytoplasm. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, immunofluorescence, deletion analysis Journal of biochemistry Medium 12869526
2004 Overexpression of HCAP1-N (common allele haplotype of GEMIN4) and HCAP1-M (minor allele haplotype) in Hep3B hepatocellular carcinoma cells suppresses colony formation and cell growth; HCAP1-M shows weaker inhibitory effect and induces differential gene expression profiles (up-regulation of proliferation genes, down-regulation of apoptosis/DNA repair genes). Transfection, colony formation assay, cell growth assay, gene expression profiling (Atlas membrane, 588 genes) Genes, chromosomes & cancer Medium 14603441
2008 A canonical nuclear localization signal (NLS) was identified in the N-terminus of Gemin4; this NLS is necessary and independently sufficient to mediate nuclear import of Gemin4. Deletion/truncation construct analysis, subcellular localization assays Biochemical and biophysical research communications Medium 18675250
2015 GEMIN4 functions as a coregulator (repressor) of the mineralocorticoid receptor (MR): GEMIN4 overexpression represses agonist-induced MR transactivation, knockdown increases expression of MR target genes, and GEMIN4 physically co-localizes with MR in the nucleus upon agonist treatment. The interaction is mediated by an MPxLxxLL motif in GEMIN4. Transient transfection reporter assay (HEK293, H9c2 cells), siRNA knockdown, endogenous gene expression (mRNA), co-localization by immunofluorescence Journal of molecular endocrinology Medium 25555524
2018 Gemin4 overexpression in human cells drives SMN and other Gemin proteins from the cytoplasm into the nucleus and disrupts subnuclear localization of the Cajal body marker coilin in a dose-dependent manner. One of three putative NLS motifs in Gemin4 is necessary and sufficient for nuclear import. Gemin4 constructs lacking this NLS sequester Gemin3 and Gemin2 in the cytoplasm but have little effect on nuclear SMN accumulation. Overexpression constructs, subcellular fractionation/imaging, NLS deletion analysis Biology open Medium 29371219
2018 Gemin4 null mice die early in embryonic development, demonstrating that Gemin4 is an essential mammalian protein required for early development (consistent with essential role in snRNP biogenesis). Heterozygous loss of Gemin4 on an SMA background did not modify SMA type I postnatal mortality. Mouse knockout (Gemin4 null), genetic crosses with SMA model mice Biology open High 29371219
2025 The micropeptide XLH-36 directly binds Gemin4, retaining it in the cytoplasm and preventing Gemin4 from promoting S100A4 mRNA splicing in the nucleus; this leads to a compensatory increase in ICAM1 and promotes EMT and TNBC metastasis. Co-immunoprecipitation/binding assay, XLH-36 knockout xenograft model, mRNA splicing assay, ICAM1/EMT readouts Oncogene Medium 41315668

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Gemin4. A novel component of the SMN complex that is found in both gems and nucleoli. The Journal of cell biology 203 10725331
2001 Association of galectin-1 and galectin-3 with Gemin4 in complexes containing the SMN protein. Nucleic acids research 153 11522829
2012 Genetic variants in the microRNA machinery gene GEMIN4 are associated with risk of prostate cancer: a case-control study of the Chinese Han population. DNA and cell biology 30 22506892
2016 Polymorphisms in GEMIN4 and AGO1 Genes Are Associated with the Risk of Lung Cancer: A Case-Control Study in Chinese Female Non-Smokers. International journal of environmental research and public health 22 27669275
2015 GEMIN4 functions as a coregulator of the mineralocorticoid receptor. Journal of molecular endocrinology 19 25555524
2018 Gemin4 is an essential gene in mice, and its overexpression in human cells causes relocalization of the SMN complex to the nucleoplasm. Biology open 18 29371219
2004 Two variants of the human hepatocellular carcinoma-associated HCAP1 gene and their effect on the growth of the human liver cancer cell line Hep3B. Genes, chromosomes & cancer 16 14603441
2016 Genetic variants in the MicroRNA biosynthetic pathway Gemin3 and Gemin4 are associated with a risk of cancer: a meta-analysis. PeerJ 10 27019773
2008 Identification and characterisation of a nuclear localisation signal in the SMN associated protein, Gemin4. Biochemical and biophysical research communications 7 18675250
2018 Anomalies in MiRNAs Machinery Gene, GEMIN-4 Variants Suggest Renal Cell Carcinoma Risk: A Small Experimental Study from North India. Indian journal of clinical biochemistry : IJCB 6 30728672
2003 HCC-associated protein HCAP1, a variant of GEMIN4, interacts with zinc-finger proteins. Journal of biochemistry 6 12869526
2017 Association of GEMIN4 gene polymorphism and the risk of cancer: a meta-analysis. OncoTargets and therapy 4 29138579
2023 GEMIN4, a potential therapeutic targets for patients with basal-like subtype breast cancer. BMC women's health 3 37507701
2024 GEMIN4 Variants: Risk Profiling, Bioinformatics, and Dynamic Simulations Uncover Susceptibility to Bladder Carcinoma. Archives of medical research 2 38401326
2021 Association of GEMIN4 gene polymorphisms with the risk of colorectal cancer in the Polish population. Polski przeglad chirurgiczny 2 35384865
2025 The novel endogenous micropeptide XLH-36 binds Gemin4 to promote triple-negative breast cancer metastasis. Oncogene 0 41315668
2003 [Inhibition of proliferation in Jurkat cells transfected with exogenous HCAP1 gene]. Zhongguo shi yan xue ye xue za zhi 0 14575535
2002 [Expression of novel cloned genes HC56, HC71 and HC90 mapped on human chromosome 17p13.3 in leukemic cells]. Zhongguo shi yan xue ye xue za zhi 0 12513740

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