Affinage

ZC3H11A

Zinc finger CCCH domain-containing protein 11A · UniProt O75152

Length
810 aa
Mass
89.1 kDa
Annotated
2026-06-11
19 papers in source corpus 9 papers cited in narrative 9 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

ZC3H11A is a stress-induced, intrinsically disordered nuclear RNA-binding protein that promotes nuclear export and processing of a subset of cellular mRNAs and is exploited by nuclear-replicating viruses (PMID:29610341, PMID:35559610). It binds short purine-rich ribonucleotide stretches through its sole structured element, an N-terminal CCCH zinc finger, with the remainder of the 810-residue protein being disordered (PMID:29610341, PMID:38969281). The protein localizes to nuclear splicing speckles and uses its zinc finger motifs both to engage target transcripts and to interact with the nuclear poly(A)-binding protein PABPN1, which controls its speckle localization; through this association ZC3H11A regulates mRNA polyadenylation (PMID:37356722). It associates tightly with the TREX mRNA-export complex, and its loss causes nuclear accumulation of target mRNAs and impairs export, underlying the dependence of HIV, influenza, HSV, adenovirus, pseudorabies virus, and porcine circovirus 2 on ZC3H11A for efficient replication (PMID:29610341, PMID:35559610). ZC3H11A is a phosphorylation substrate of the ERK1/2-downstream kinases RSK1 and RSK4 (PMID:38342435). In vivo, Zc3h11a is essential for early mouse embryogenesis, where it maintains expression of glycolytic and fatty-acid metabolic genes and mitochondrial function (PMID:37252988); its loss in tumor and tissue contexts engages immunogenic cell death and antigen-presentation pathways (PMID:39582529) and, in the eye, links to high myopia with dysregulated PI3K-AKT and NF-κB signaling (PMID:40864167).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2009 Low

    An initial interaction screen placed ZC3H11A in the nuclear pre-mRNA processing machinery by linking it to a core splicing factor, raising the question of whether it acts in splicing or splicing-factor localization.

    Evidence Yeast two-hybrid identifying interaction with U2AF65 (U2AF2)

    PMID:19540372

    Open questions at the time
    • Single yeast two-hybrid with no biochemical confirmation
    • Functional consequence of the interaction untested
    • No mapping of interaction surface
  2. 2018 High

    Defined ZC3H11A's core molecular activity: a stress-induced speckle-localized RNA-binding protein that binds purine-rich motifs and is required for nuclear mRNA export, explaining why nuclear- but not cytoplasmic-replicating viruses depend on it.

    Evidence CRISPR/Cas9 knockout, CLIP-seq, immunofluorescence, and nuclear export assays in HeLa cells during adenovirus infection

    PMID:29610341

    Open questions at the time
    • Export machinery partners not yet identified
    • Cellular (non-viral) mRNA targets not defined
    • Mechanism coupling RNA binding to export step unresolved
  3. 2022 Medium

    Connected ZC3H11A's export function to a defined machinery by showing it associates with the TREX complex, and that this role is conserved and supports nuclear-replicating virus growth in a non-human system.

    Evidence CRISPR/Cas9 knockout, Co-IP with TREX complex, and viral growth assays in porcine PK-15 cells

    PMID:35559610

    Open questions at the time
    • Direct vs indirect TREX contact not resolved
    • Single lab, orthologous system
    • Which TREX subunit ZC3H11A binds unknown
  4. 2023 High

    Identified PABPN1 as a key partner that localizes ZC3H11A to speckles and revealed a second molecular function—regulation of mRNA polyadenylation—mediated by the same zinc finger motifs used for RNA binding.

    Evidence Co-IP interactome, RNA immunoprecipitation, zinc-finger mutagenesis, and polyadenylation assays in KO cells

    PMID:37356722

    Open questions at the time
    • Whether polyadenylation control extends to cellular transcripts beyond viral mRNA unclear
    • Mechanism by which PABPN1 directs speckle localization not detailed
    • Relationship between export and polyadenylation roles unresolved
  5. 2023 High

    Established the physiological essentiality of ZC3H11A, showing it is required for early embryogenesis through maintenance of metabolic gene expression and mitochondrial function, linking its mRNA-handling activity to a developmental program.

    Evidence Constitutive/conditional KO mice, CLIP-seq, proteomic interactome, transcriptomics, and mitochondrial/differentiation assays in embryonic stem cells

    PMID:37252988

    Open questions at the time
    • Direct mRNA targets driving the metabolic phenotype not pinpointed
    • Whether lethality reflects export vs polyadenylation defect unclear
    • Causal link between mitochondrial defect and lethality not established
  6. 2024 Medium

    Placed ZC3H11A as a downstream node of the ERK1/2 MAPK pathway by identifying it as a direct RSK1/RSK4 phosphorylation substrate, introducing a potential regulatory input to its activity.

    Evidence Analog-sensitive kinase substrate identification with mutagenesis and inhibitor validation

    PMID:38342435

    Open questions at the time
    • Functional consequence of phosphorylation not determined
    • Phosphosites' effect on RNA binding or localization untested
    • In vivo relevance of the modification unknown
  7. 2024 Medium

    Characterized the protein architecture, showing ZC3H11A is largely intrinsically disordered with only the N-terminal zinc finger structured, and that Cys8 contributes to protein stability rather than nucleic acid binding.

    Evidence Recombinant expression in Sf9/E. coli, Cys8 mutagenesis, and size-exclusion chromatography

    PMID:38969281

    Open questions at the time
    • Functional role of oligomeric states untested
    • No high-resolution structure of the zinc finger-RNA complex
    • Role of disordered region in partner binding unmapped
  8. 2024 Medium

    Revealed a cell-fate consequence of ZC3H11A loss: depletion triggers interferon, antigen presentation, and immunogenic cell death, with antitumor effect in vivo, positioning it as a survival/immune-evasion factor.

    Evidence ASO and shRNA knockdown with flow cytometry, ELISA, and an in vivo B16 melanoma model

    PMID:39582529

    Open questions at the time
    • Molecular link between mRNA-export role and apoptosis/IFN induction not defined
    • Direct effector transcripts unknown
    • Single-lab in vivo result
  9. 2025 Medium

    Linked ZC3H11A to a human Mendelian-type phenotype, high myopia, with a KO mouse recapitulating ocular pathology and implicating negative regulation of PI3K-AKT and NF-κB signaling.

    Evidence Whole exome sequencing of a human cohort plus Zc3h11a KO mouse with ERG, histology, retinal RNA-seq, qPCR, and western blotting

    PMID:40864167

    Open questions at the time
    • Causal mechanism connecting RNA-handling to myopia unresolved
    • Pathway placement rests on expression/western readouts
    • Direct retinal mRNA targets not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZC3H11A's RNA-export and polyadenylation activities are mechanistically integrated, and how phosphorylation, oligomerization, and partner binding tune target selection across development, immunity, and disease, remains unresolved.
  • No unified model coupling export, polyadenylation, and metabolic gene regulation
  • Direct cellular mRNA target set across contexts undefined
  • Functional output of RSK phosphorylation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-9609507 Protein localization 2
Partners
PABPN1RPS6KA1RPS6KA6U2AF2
Complex memberships
TREX complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During adenovirus infection, ZC3H11A and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription occur. CLIP-seq showed ZC3H11A binds short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. In ZC3H11A knockout HeLa cells, adenovirus fiber mRNA accumulates in the nucleus, demonstrating that RNA-binding is required for ZC3H11A's role in nuclear mRNA export. Multiple nuclear-replicating viruses (HIV, influenza, HSV, adenovirus) but not cytoplasmic-replicating viruses depend on ZC3H11A for efficient growth. CRISPR/Cas9 knockout, CLIP-seq (cross-linking immunoprecipitation sequencing), immunofluorescence/localization, RNA nuclear export assay Proceedings of the National Academy of Sciences of the United States of America High 29610341
2009 ZC3H11A interacts with the splicing factor U2AF65 (U2AF2) as identified by yeast two-hybrid screening, suggesting a role in pre-mRNA splicing or U2AF65 sub-nuclear localization. Yeast two-hybrid Biochimica et biophysica acta Low 19540372
2023 ZC3H11A protein interacts specifically with the nuclear poly(A)-binding protein PABPN1, which controls ZC3H11A localization into nuclear speckles. ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and with adenovirus (HAdV-5) capsid mRNA. Loss of ZC3H11A alters polyadenylation of HAdV-5 capsid mRNA, indicating ZC3H11A acts as a novel regulator of mRNA polyadenylation. Co-immunoprecipitation (ZC3H11A interactome), RNA immunoprecipitation, mutagenesis of zinc finger motifs, polyadenylation assay in KO cells The Journal of biological chemistry High 37356722
2023 Zc3h11a is essential for mouse embryonic viability; homozygous KO embryos degenerate around implantation (E6.5). Proteomic analysis in embryonic stem cells showed ZC3H11A tightly interacts with mRNA-export proteins. CLIP-seq demonstrated ZC3H11A binds a subset of mRNAs critical for metabolic regulation. Loss of Zc3h11a dysregulates glycolysis and fatty acid metabolic pathways (transcriptomics at E4.5), impairs differentiation toward epiblast-like cells, and reduces mitochondrial membrane potential in embryonic stem cells. Conditional and constitutive CRISPR/Cas9 knockout mice, transcriptomics, proteomics (interactome), CLIP-seq, mitochondrial membrane potential assay, in vitro differentiation assay Proceedings of the National Academy of Sciences of the United States of America High 37252988
2022 Porcine ZC3H11A interacts with the TREX (transcription and export) complex and is required for mRNA export in pig cells. Knockout of porcine ZC3H11A via CRISPR/Cas9 significantly inhibits proliferation of pseudorabies virus (PRV) and porcine circovirus 2 (PCV2), consistent with a conserved role in mRNA export supporting nuclear-replicating virus growth. CRISPR/Cas9 knockout in PK-15 cells, Co-IP with TREX complex, viral growth assay ACS infectious diseases Medium 35559610
2024 ZC3H11A is a phosphorylation substrate of both RSK1 and RSK4 serine/threonine kinases (downstream of ERK1/2 MAPK pathway), as identified by analog-sensitive kinase strategy and validated by mutagenesis and kinase inhibitors. Analog-sensitive kinase substrate identification, mutagenesis, kinase inhibitor validation The Journal of biological chemistry Medium 38342435
2024 ZC3H11A is an extensively intrinsically disordered protein (810 aa) with only the N-terminal zinc finger domain (aa 1–86) being well structured. Substitution of Cys8 in the zinc finger did not abolish nucleic acid binding but stabilized the full-length protein. The protein forms monomers, dimers, tetramers and hexamers in solution. Recombinant protein expression (Sf9 insect cells, E. coli), mutagenesis (Cys8→Ala/Ser), size-exclusion chromatography, structural characterization Protein expression and purification Medium 38969281
2024 Knockdown of ZC3H11A using antisense oligonucleotides (ASO) or shRNA upregulates MHC class I antigen presentation, increases IFN-β secretion, induces apoptosis (caspase activation, annexin V), and triggers immunogenic cell death (calreticulin surface exposure, ATP secretion) leading to dendritic cell phagocytosis and maturation. Constitutive shRNA knockdown in B16 melanoma cells reduces tumor growth and prolongs survival in mice. ASO knockdown, shRNA lentiviral knockdown, flow cytometry (MHC I, annexin V, calreticulin), ELISA (IFN-β, ATP), in vivo tumor model Molecular therapy. Nucleic acids Medium 39582529
2025 Missense mutations in ZC3H11A are associated with high myopia in humans. Zc3h11a KO mice develop myopia with upregulation of Tgfβ1, Mmp2, and Il6 in retina/sclera, bipolar cell dysfunction and loss, and ultrastructural abnormalities. Retinal transcriptomics identified 769 differentially expressed genes, and qPCR/western blotting confirmed ZC3H11A negatively regulates the PI3K-AKT and NF-κB signaling pathways. Whole exome sequencing (human cohort), Zc3h11a KO mouse model, electroretinography, immunofluorescence, transmission electron microscopy, retinal RNA-seq, qPCR, western blotting eLife Medium 40864167

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature genetics 121 25038754
2012 Genetic variants on chromosome 1q41 influence ocular axial length and high myopia. PLoS genetics 92 22685421
2020 Role of CCCH-Type Zinc Finger Proteins in Human Adenovirus Infections. Viruses 33 33217981
2018 Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proceedings of the National Academy of Sciences of the United States of America 33 29610341
2009 Interactome for auxiliary splicing factor U2AF(65) suggests diverse roles. Biochimica et biophysica acta 30 19540372
2013 Selection of new appropriate reference genes for RT-qPCR analysis via transcriptome sequencing of cynomolgus monkeys (Macaca fascicularis). PloS one 22 23613744
2018 A Novel Approach for Identifying Relevant Genes for Breast Cancer Survivability on Specific Therapies. Evolutionary bioinformatics online 15 30116102
2021 Integration of Imaging Genomics Data for the Study of Alzheimer's Disease Using Joint-Connectivity-Based Sparse Nonnegative Matrix Factorization. Journal of molecular neuroscience : MN 12 34410569
2023 Ablation of ZC3H11A causes early embryonic lethality and dysregulation of metabolic processes. Proceedings of the National Academy of Sciences of the United States of America 11 37252988
2022 Gain of Chromosome 1q Perturbs a Competitive Endogenous RNA Network to Promote Melanoma Metastasis. Cancer research 11 36052492
2023 Analysis of cancer-associated fibroblasts in cervical cancer by single-cell RNA sequencing. Aging 10 38157264
2023 The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts. The Journal of biological chemistry 8 37356722
2019 In silico analysis of human renin gene-gene interactions and neighborhood topologically associated domains suggests breakdown of insulators contribute to ageing-associated diseases. Biogerontology 6 31520345
2022 Porcine ZC3H11A Is Essential for the Proliferation of Pseudorabies Virus and Porcine Circovirus 2. ACS infectious diseases 5 35559610
2024 Identification of RSK substrates using an analog-sensitive kinase approach. The Journal of biological chemistry 3 38342435
2023 Analysis of the mRNA export protein ZC3H11A in HCMV infection and pan-cancer. Frontiers in microbiology 3 38033582
2024 Targeting ZC3H11A elicits immunogenic cancer cell death through augmentation of antigen presentation and interferon response. Molecular therapy. Nucleic acids 2 39582529
2025 ZC3H11A mutations cause high myopia by triggering PI3K-AKT and NF-κB-mediated signaling pathway in humans and mice. eLife 0 40864167
2024 Production of stable and pure ZC3H11A - An extensively disordered RNA binding protein. Protein expression and purification 0 38969281

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